Cyclotide genes in the fabaceae plant family

ABSTRACT

The present invention relates to cyclotides and cyclotide-encoding genes from the Fabaceae plant family, and to the expression of cyclotides in Fabaceae. The present invention further relates to isolated nucleic acids configured to express cyclotides comprising heterologous peptide grafts in plants of the Fabaceae family.

This application claims priority to U.S. Provisional Application Ser. No. 61/466,888, filed Mar. 23, 2011, which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to cyclotides and cyclotide genes from the Fabaceae plant family, and to the expression of cyclotides in Fabaceae. The present invention further relates to isolated nucleic acids configured to express cyclotides comprising heterologous peptide grafts in plants of the Fabaceae family.

BACKGROUND OF THE INVENTION

Cyclotides are a topologically unique family of plant proteins that are exceptionally stable (Craik, D. J., et al., (1999) J. Mol. Biol. 294, 1327-1336). They comprise ˜30 amino acids arranged in a head-to-tail cyclized peptide backbone that additionally is restrained by a cystine knot motif associated with six conserved cysteine residues. The cystine knot (Pallaghy, P. K., Nielsen, K. J., Craik, D. J. & Norton, R. S. (1994) Protein Sci. 3, 1833-1839) is built from two disulfide bonds and their connecting backbone segments forming an internal ring in the structure that is threaded by the third disulfide bond to form an interlocking and cross braced structure (FIG. 1). Superimposed on this cystine knot core motif are a well-defined β-sheet and a series of turns displaying short surface-exposed loops.

Cyclotides express a diversity of peptide sequences within their backbone loops and have a broad range of biological activities, including uterotonic (Gran, L. (1970) Medd. Nor. Farm. Selsk. 12, 173-180), anti-HIV (Gustafson, K. R., Sowder, R. C. I., Henderson, L. E., Parsons, I. C., Kashman, Y., Cardellina, J. H. I., McMahon, J. B., Buckheit, R. W. J., Pannell, L. K. & Boyd, M. R. (1994) J. Am. Chem. Soc. 116, 9337-9338), antimicrobial (Tam, J. P., Lu, Y. A., Yang, J. L. & Chiu, K. W. (1999) Proceedings of the National Academy of Sciences of the United States of America 96, 8913-8918), and anticancer activities (Svångard, E., Burman, R., Gunasekera, S., Lovborg, H., Gullbo, J. & Göransson, U. (2007) J Nat Prod 70, 643-7). They are thus of great interest for pharmaceutical applications. Some plants from which they are derived are used in indigenous medicines, including kalata-kalata, a tea from the plant Oldenlandia affinis that is used for accelerating childbirth in Africa that contains the prototypic cyclotide kalata B1 (Gran, L. (1973) Lloydia 36, 174-178). This ethnobotanical use and more recent biophysical studies (Colgrave, M. L. & Craik, D. J. (2004) Biochemistry 43, 5965-5975) illustrate the remarkable stability of cyclotides, i.e., they survive boiling and ingestion, observations unprecedented for conventional peptides. Their exceptional stability means that they have attracted attention as potential templates in peptide-based drug design applications (Craik, D. J. (2006) Science 311, 1563-1564). In particular, the grafting of bioactive peptide sequences into a cyclotide framework offers the promise of a new approach to stabilize peptide-based therapeutics, thereby overcoming one of the major limitations on the use of peptides as drugs. Chemical (Daly, N. L., Love, S., Alewood, P. F. & Craik, D. J. (1999) Biochemistry 38, 10606-14; Tam, J. P. &Lu, Y.-A. (1998) Protein Sci. 7, 1583-1592), chemo-enzymatic (Thongyoo, P., Roque-Rosell, N., Leatherbarrow, R. J. & Tate, E. W. (2008) Org Biomol Chem 6, 1462-1470), and recombinant (Camarero, J. A., Kimura, R. H., Woo, Y.-H., Shekhtman, A. & Cantor, J. (2007) ChemBioChem 8, 1363-1366) approaches to the synthesis of cyclotides have been developed, thus facilitating these pharmaceutical applications. See also WO 01/27147 to Craik, et al, and WO 01/34829 to Craik, et al., each incorporated herein by reference.

One issue with expressing cyclotides in different host plants is ensuring that the host plant has the necessary cellular machinery to process the expressed polypeptides to produce mature cyclic molecules. One approach is to identify host plant families that produce naturally occurring cyclotides, and to adapt the natural genes to facilitate the expression of foreign or engineered cyclotides (e.g., cyclotides from other plant families, or cyclotides engineered to contain one or more grafted peptide sequences). Until recently cyclotides had been found only in the Rubiaceae (coffee) and Violaceae (violet) plant families (Kaas, Q., Westermann, J. C. & Craik, D. J. (2010) Toxicon 55, 1491-509), apart from two atypical members in the Cucurbitaceae (cucurbit) family (Chiche, L., Heitz, A., Gelly, J. C., Gracy, J., Chau, P. T., Ha, P. T., Hernandez, J. F. & Le-Nguyen, D. (2004) Curr Protein Pept Sci 5, 341-349). Cyclotides from the Rubiaceae and Violaceae are biosynthesized via processing from dedicated precursor proteins encoded by multi-domain genes which contain one, two or three cyclotide domains (Dutton, J. L., Renda, R. F., Waine, C., Clark, R. J., Daly, N. L., Jennings, C. V., Anderson, M. A. & Craik, D. J. (2004) J. Biol. Chem. 279, 46858-46867).

There remains a need for expression systems configured to express foreign and modified cyclotides in additional plant families.

SUMMARY OF THE INVENTION

The present invention provides systems and methods for producing cyclotides in plants of the Fabaceae family. In some embodiments, the present invention provides isolated genes encoding cyclotides of the Fabaceae family, while in some embodiments, the present invention provides expression systems making use of Fabaceae cyclotide genetic framework for the expression of foreign or modified cyclotides in plants of the Fabaceae family.

In some embodiments, the present invention provides an isolated nucleic acid molecule comprising a sequence of nucleotides encoding a precursor form of a cystine knot polypeptide (e.g., a linear polypeptide), wherein the amino acid sequence of the precursor form comprises a signal peptide, a cystine knot polypeptide, and a non-cystine knot polypeptide, wherein the cystine knot polypeptide in its mature form comprises the structure:

-   -   wherein C₁ to C₆ are cysteine residues;     -   wherein each of C₁ and C₄, C₂ and C₅, and C₃ and C₆ are         connected by a disulfide bond to form a cystine knot;     -   wherein each X represents an amino acid residue in a loop,         wherein the amino acid residues may be the same or different;         -   wherein d is about 1-2;         -   wherein for a, b, c, e, and f, and         -   i) a may be any number from 3-10, and         -   ii) b, c, e, and f may be any number from 1 to 20.

In certain embodiments, in the isolated nucleic acid molecule described above, a is from about 3 to 6, b is from about 3 to about 5, c is from about 2 to about 7, e is from about 3 to about 6 and f is from about 4 to about 9. In some embodiments, a is about 3, b is about 4, c is from about 4 to about 7, d is about 1, e is about 4 or 5 and f is from about 4 to about 7.

In some embodiments, in the precursor form of a cystine knot polypeptide, the sequence of at least one cystine knot polypeptide comprises on at least one end an amino acid triplet selected from the group consisting of GLP, GIP, and SLP. In certain preferred embodiments, in the cyclic form of the cystine knot polypeptide, loop 6 of the encoded polypeptide has an amino acid sequence selected from the group consisting of YRNGVIP (SEQ ID NO:110), YLNGVIP (SEQ ID NO:111), YLDGVP (SEQ ID NO:112), YLNGIP (SEQ ID NO:113), YLDGIP (SEQ ID NO:114), YLNGLP (SEQ ID NO:115), YNNGLP (SEQ ID NO:116), YNDGLP (SEQ ID NO:117), YINGTVP (SEQ ID NO:118), YIDGTVP (SEQ ID NO:119), YNHEP (SEQ ID NO:120), YDHEP (SEQ ID NO:121), LKNGSAF (SEQ ID NO:122), MKNGLP (SEQ ID NO:123), YRNGIP (SEQ ID NO:124), YKNGIP (SEQ ID NO:125, and YRDGVIP (SEQ ID NO:126).

In some embodiments, the cystine knot polypeptide portion of said linear precursor comprises the structure:

-   -   Z₁ C₁(X_(1 . . .) X_(a))C₂(X^(I) _(1 . . .) X^(I) _(b))C₃(X^(II)         _(1 . . .) X^(II) _(c))C₄(X^(III) _(1 . . .) X^(III)         _(d))C₅(X^(IV) _(1 . . .) X^(IV) _(e))C₆Z₂         -   wherein C₁ to C₆ are cysteine residues;         -   wherein each of C₁ and C₄, C₂ and C₅, and C₃ and C₆ are             connected by a disulfide bond to form a cystine knot,         -   wherein each X represents an amino acid residue in a loop,             wherein said amino acid residues may be the same or             different;             -   wherein d is about 1-2;             -   wherein for a, b, c, and e, and             -   i) a may be any number from 3-10, and             -   ii) b, c, and e may be any number from 1 to 20 and                 wherein Z₁ is GVP, GIP, GVIP, GLP, HEP, GTVP, or GSA,                 and Z₂ is YLN, YLD, YKN, YRN, YNN. YND, TN, TD, YRD,                 YIN, MKN, or LKN.

In some embodiments of the encoded precursor form of the cystine knot polypeptide, a linker peptide comprising two or more amino acids connects the non-cystine knot polypeptide with the C-terminal amino acid of the sequence that forms the mature form of the cystine knot polypeptide. The non-cystine knot polypeptide may comprise a protein associated with a different function in an organism (e.g., a protein such as albumin, known to have functions that are not typically associated with or requiring the presence of a cyclic cystine knot peptide). In certain preferred embodiments, the non-cystine knot polypeptide comprises an albumin or albumin-like polypeptide, and the CCK portion replaces a portion of a typical albumin polypeptide sequence. In some particularly preferred embodiment, the albumin polypeptide comprises an albumin-1 a-chain and the CCK portion replaces some or, all of the b-chain portion of the albumin-1 polypeptide.

As used herein, the “signal” peptide generally refers to an endoplasmic reticulum (ER) signal sequence, typically of about 24 amino acids. (Emanuelssson, O., Brunak, S., von Heijne, G., Nielsen H. (2007) Nature Protocols, 2, 953-971) In certain embodiments, in the isolated nucleic acid molecule described above, in the amino acid sequence of the precursor form the signal peptide is contiguous with the N-terminal amino acid of the sequence that makes up the mature form of the cystine knot polypeptide. In particularly preferred embodiments, the isolated nucleic acid molecule comprising a sequence encoding a precursor form of a cystine knot polypeptide is from a plant belong to the family Fabaceae. In certain particularly preferred embodiments, the nucleic acid sequence encoding the precursor form of a cystine knot polypeptide is from Clitoria ternatea. In some embodiments, the signal peptide is encoded by a nucleotide sequence comprising ATGGCTTACGTTAGACTTACTTCTCTTGCCGTTCTCTTCTTCCTTGCTGCTTCCGTT ATGAAGACAGAAGGA (JF501210) (SEQ ID NO:127), while in some embodiments, the signal peptide is encoded by a nucleic acid sequence selected from SEQ ID NOS:150, 152, 154, 156, 158, and 160. In some embodiments, the isolated nucleic acid encodes a signal peptide comprising the amino acid sequence MAYVRLTSLAVLFFLAASVMKTEG (JF501210) (SEQ ID NO:128), while in some embodiments, the isolated nucleic acid encodes a signal peptide having an amino acid sequence selected from SEQ ID NOS:151, 153, 155, 157, 159 and 161.

In some embodiments, the present invention provides an isolated nucleic acid molecule encoding a proteinaceous molecule having a cyclic cystine knot backbone and a defined biological activity, comprising a sequence of nucleotides encoding a precursor form of a cystine knot polypeptide operably linked to a promoter, wherein the amino acid sequence of the precursor form comprises a signal peptide, a cystine knot polypeptide and a non-cystine knot polypeptide, wherein the cystine knot polypeptide in its mature form comprises the structure:

wherein C₁ to C₆ are cysteine residues and each of C₁ and C₄, C₂ and C₅, and C₃ and C₆ are connected by a disulfide bond to form a cystine knot, and wherein each X represents an amino acid residue in a loop, which may be the same or different. In certain preferred embodiments, d is about 1-2 and one or more of loops 1, 2, 3, 5 or 6 have an amino acid sequence comprising the sequence of a heterologous peptide comprising a plurality of contiguous amino acids and having a defined biological activity, the peptide being generally about 2 to 30 amino acid residues, such that any loop comprising the sequence of the peptide comprises 2 to about 30 amino acids, and such that for any of loops 1, 2, 3, 5, or 6 that do not contain the sequence of the peptide, a, b, c, e, and f, may be the same or different, and a may be any number from 3-10, and b, c, e, and f may be any number from 1 to 20.

In some embodiments of the isolated nucleic acid described above, the amino acid sequence of the heterologous peptide comprises a portion of an amino acid sequence of a larger protein, wherein the heterologous peptide confers the defined biological activity on the larger protein.

In some embodiments of the isolated nucleic acid described above, for any of loops 1, 2, 3, 4, 5, or 6 that do not contain the sequence of the heterologous peptide, a is from about 3 to 6, b is from about 3 to about 5, c is from about 2 to about 7, d is about 1 to 2, e is from about 3 to about 6 and f is from about 4 to about 9. In some preferred embodiments, a is about 3 and d is about 1, and for any of loops 2, 3, 5, or 6 that do not contain the sequence of the heterologous peptide, b is about 4, c is from about 4 to about 7, e is about 4 or 5 and f is from about 4 to about 7. In certain particularly preferred embodiments, a is about 6 and d is about 1, and for any of loops 2, 3, 5, or 6 that do not contain the sequence of the heterologous peptide, b is about 5, c is about 3, e is from about 5 and f is from about 8.

In some embodiments, any loop comprising the sequence of the heterologous peptide comprises 2 to about 20 amino acids, more preferably 2 to about 10 amino acids.

In certain embodiments of the isolated nucleic acid described above, when the encoded cystine knot polypeptide is processed into a cyclic form, loop 6 comprises an amino acid sequence selected from the group consisting of YRNGVIP (SEQ ID NO:110), YLNGVIP (SEQ ID NO:111), YLDGVP (SEQ ID NO:112), YLNGIP (SEQ ID NO:113), YLDGIP (SEQ ID NO:114), YLNGLP (SEQ ID NO:115), YNNGLP (SEQ ID NO:116), YNDGLP (SEQ ID NO:117), YINGTVP (SEQ ID NO:118), YIDGTVP (SEQ ID NO:119), YNHEP (SEQ ID NO:120), YDHEP (SEQ ID NO:121), LKNGSAF (SEQ ID NO:122), MKNGLP (SEQ ID NO:123), YRNGIP (SEQ ID NO:124), YKNGIP (SEQ ID NO:125, and YRDGVIP (SEQ ID NO:126).

In some embodiments of the isolated nucleic acid molecule the non-cystine knot polypeptide comprises an albumin-1 polypeptide and in certain preferred embodiments, the albumin polypeptide comprises an albumin-1 a-chain.

In some embodiments of the isolated nucleic acid molecule, in the encoded amino acid sequence of the precursor form, the signal peptide is adjacent to the N-terminal amino acid of the mature form of the cystine knot polypeptide.

In some embodiments the present invention provides a composition comprising a host cell comprising a heterologous nucleic acid comprising an isolated nucleic acid as described above. In some embodiments, the host cell is a plant cell, and in certain preferred embodiments, the plant cell is from the plant family Fabaceae. In particularly preferred embodiments, the host cell carries an enzyme for processing a precursor form of the cystine knot polypeptide expressed from the nucleic acid to produce a cyclic cystine knot polypeptide.

In some embodiments, the present invention provides a method for producing a cystine knot polypeptide comprising transforming a host cell with a vector comprising a nucleic acid molecule as described above and the precursor form of the cystine knot polypeptide is expressed in the host cell.

In some embodiments the present invention provides methods for producing a cyclic cystine knot polypeptide, comprising: transforming a host cell with a vector comprising a nucleic acid molecule as described above; expressing a linear precursor form of a cyclic cystine knot polypeptide; and processing the linear precursor form to form a mature cyclic cystine knot polypeptide having the structure:

In some embodiments, when the cystine knot polypeptide is processed into a cyclic form, loop 6 comprises an amino acid sequence selected from the group consisting of YRNGVIP (SEQ ID NO:110), YLNGVIP (SEQ ID NO:111), YLDGVP (SEQ ID NO:112), YLNGIP (SEQ ID NO:113), YLDGIP (SEQ ID NO:114), YLNGLP (SEQ ID NO:115), YNNGLP (SEQ ID NO:116), YNDGLP (SEQ ID NO:117), YINGTVP (SEQ ID NO:118), YIDGTVP (SEQ ID NO:119), YNHEP (SEQ ID NO:120), YDHEP (SEQ ID NO:121), LKNGSAF (SEQ ID NO:122), MKNGLP (SEQ ID NO:123), YRNGIP (SEQ ID NO:124), YKNGIP (SEQ ID NO:125, and YRDGVIP (SEQ ID NO:126).

In some embodiments, the host cell is a plant cell, and in certain preferred embodiments, the plant cell is from the plant family Fabaceae. In particularly preferred embodiments, the host cell carries an enzyme for processing the precursor form of the cystine knot polypeptide to produce a cyclic cystine knot polypeptide. In some embodiments, a linear form of the cystine knot polypeptide is cyclized in vitro using, e.g., enzymatic and/or chemical treatment.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 provides a diagram illustrating the botanical and geographical origins of the first cyclotides described from Rubiaceae, Violaceae and Fabaceae plant families.

FIG. 2 provides MALDI-TOF spectra indicating the presence of cyclotides in C. ternatea seed extract. Offset-aligned MALDI-TOF spectra of ‘native’ (A) and ‘reduced and carbamidomethylated’ (B) putative cyclotide species, Cter A.

FIG. 3 provides nanospray tandem MS fragmentation patterns for ‘native’ vs. chemically modified Cter A at a collision energy setting of 50 V. (A) ‘Native’ (cyclic oxidized) cyclotide precursor m/z 1090.1, (B) cyclic reduced and alkylated precursor m/z 1206.1, (C) linear reduced and alkylated precursor m/z 1212.1. These apparent triply-charged fragment ions correspond to species of molecular masses 3267 Da, 3615 Da and 3633 Da, respectively.

FIG. 4 provides nanospray sequencing of Cter B. Left panel: Digestion scheme and mass of proteolytic fragments. (A) TOF-MS spectrum of combined trypsin and endoproteinase Glu-C digest. The peaks are labelled according to their charge state, where B²⁺, B³⁺ and B⁴⁺ correspond to the full-length linearized Cter B, and C³⁺ and D²⁺ signify smaller fragments produced through cleavage of the cyclic precursor at two points along the peptide backbone. (B) MS/MS of precursor 1092.4³⁺ (3274.2 Da). (C) MS/MS of precursor 628.5³⁺ (1882.6 Da). (D) MS/MS of precursor 705.7²⁺ (1409.4 Da).

FIG. 5 provides a “sequence logo” relative frequency plot of the amino acids in the first 12 C. ternatea cyclotides listed in Table 1. Conserved residues among sequences include Pro4, CysS, Glu7, Cys9, Ile12, Pro13, Cys14, Thr15, Cys22, Ser23, Cys24, Lys25, Lys27, Val28, Cys29 and Tyr30.

FIG. 6 shows isotopic distribution delineating isoform-specific sequence ions. Nanospray spectra for reduced and digested (trypsin and endoproteinase Glu-C) Cter B. (A) TOF-MS spectrum of full-length linearized Cter B-precursor 3274.2 Da. (B) TOF-MS spectrum of Cter B digest product with precursor 628.5³⁺ (1882.6 Da). (C) TOF-MS spectrum of Cter B digest product with precursor 705.7²⁺ (1409.4 Da). (D) Full product ion spectrum of precursor m/z 705.7²⁺ (1409.4 Da). Sequence ions shown in bold represent cleavage of the amide bonds either side of the amino acid at position 7. (E) Isotopic distributions of diagnostic fragment ions b6, b7, y6 and y7 indicate the presence of both Asn and Asp at position 7 and thus the heterogeneous nature of the selected precursor ion within the transmission window. Dotted lines illustrate the theoretical isotopic distributions for precursor and fragment ions, assuming that the residue at position 7 is an asparagine. Arrows indicate the observed intensities of labelled monoisotopic peaks.

FIG. 7 illustrates distribution of ribosomally synthesized circular proteins within angiosperms. Cyclotide-containing plant families as reported in the literature appear in red italicized font. *A recent study reported evidence of cyclotides within the Apocynaceae family (Gruber, C. W., et al., (2008) Plant Cell 20, 2471-2483), but no cyclotide peptide or nucleic acid sequences have been published yet. ^(‡)Gene sequences encoding putative linear cyclotide-like proteins have been identified in several species within the Poaceae family. (These sequences lack the C-terminal Asn or Asp considered crucial for in planta cyclization). ^(†)Backbone-cyclized circular peptides distinct from cyclotides have been characterized from species within the Asteraceae family.

FIG. 8 provides a sequence alignment of the prototypical cyclotide kalata B1 (kB1) from the Rubiaceae plant Oldenlandia affinis with other selected cyclotide sequences. The six conserved cysteine residues are labeled with Roman numerals and various loops in the backbone between these cysteines are labeled loops 1-6. The cystine knot arrangement is indicated. The sequences of kalata B1 (SEQ ID NO:4, Saether, O., et al. (1995) Biochemistry 34:4147-4158), cycloviolacin O2 (SEQ ID NO:5, Craik, D. J., et al., (1999) J Mol Biol 294:1327-1336), MCoTI-II (SEQ ID NO:6, Hernandez J.-F., et al. (2000) Biochemistry 39:5722-5730) and Cter A (SEQ ID NO:7, Poth, A. G., et al., (2011) ACS Chem. Biol. 10.1021/cb100388j) represent examples of cyclotides isolated from the Rubiaceae, Violaceae, Cucurbitaceae and Fabaceae plant families. The conserved cysteines are boxed and their location on the structure is indicated by the dotted arrows. The putative processing points by which mature cyclotides are excised from their precursor proteins are indicated and correspond to an N terminal glycine residue and a C terminal Asn (N) or Asp (D) residue. PDB ID code for kalata B1 is 1NB1.

FIG. 9 provides a CLUSTAL 2.1 multiple sequence alignment of nineteen cyclotides from seeds, leaves and flowers of C. ternatea. Identical amino acids are indicated by “*”, strongly similar amino acids are indicated by “:” and similar amino acids are indicated by “.”.

FIG. 10 provides a schematic representation of the complete cDNA sequence (SEQ ID NO:27) and putative translated protein sequence (SEQ ID NO:28) for the Cter M isolate from leaf tissue of butterfly pea (Clitoria ternatea). The site of initial degenerate primer Ct-For1A is shown in lower case letters, and gene-specific primers used for 5′ RACE are italicized. The mature cyclotide peptide is double underlined and the putative albumin-1 a-chain domain is single-underlined.

FIG. 11A provides a comparison of several genes encoding kalata cyclotides in the Rubiaceae plant Oldenlandia affinis.

FIG. 11B provides a comparison of the gene structures for two Fabaceae family albumin genes [Glycine max (soybean) albumin-1 and Pisum savitum (green pea) albumin-1] with the gene encoding the Cter M cyclotide isolate from C. ternatea.

FIG. 12 compares the gene structures for an exemplary kalata cyclotide gene from O. affinis (encoding kB3/6), the gene encoding the Cter M cyclotide isolate from C. ternatea, and the Pisum savitum albumin-1 gene.

FIG. 13 provides an alignment of several complete and partial precursor cyclotide polypeptides from C. ternatea.

FIG. 14 shows the NMR spectra and three-dimensional structure of Cter M. (A) One-dimensional spectra of Cter M recorded before (top) and after (bottom) heating to 95° C. for 5 minutes. (B) Superposition of the 20 lowest energy structures of Cter M. Secondary structure of Cter M (C) and PA1b (E; PDB code 1P8B). The strands are shown as arrows and the helical turns as thickened ribbons. The disulfide bonds are shown in ball-and-stick format. The structure figures were generated using MOLMOL (Koradi, R., Billeter, M. & Wüthrich, K. (1996) J. Mol. Graph. 14, 29-32). Superimposition of Cter M and PA1b (D) showing cystine knot motif; disulfide bonds are indicated, and the aC are represented by spheres.

FIG. 15 provides a graph comparing haemolytic activity of Cter M with the prototypic cyclotide kalata B1 and the known pore-forming agent from bee venom, melittin.

FIG. 16 illustrates the results following exposure of nematodes to control (no peptide) and Cter M cyclotide solutions. The effect of Cter M of the motility of L3 larvae of Haemonchus contortus: control worms (A) and cyclotide treated worms (B).

FIG. 17 illustrates the effect of Cter M and kB1 on the growth of Helicoverpa armigera. The weight of larvae at 0, 24 and 48 h is plotted versus peptide concentration for Cter M (A) and kB1 (B) and the size of control larvae (bottom, right) alongside larvae fed at medium (0.25 μmol/g diet) (top, right) and high (1.0 μmol/g diet)(top, left) peptide concentrations at 48 h is depicted for Cter M (C) and kB1 (D).

FIG. 18 shows a ClustalW2 alignment of Cter M with BLASTP- and TBLASTN-matched Fabaceae albumin-I precursor proteins, in order from Accession ID No. CAA11040.1 (SEQ ID NO:37) to Accession No. BT053249.1 (SEQ ID NO:103), followed by Cter M (SEQ ID NO:28). N-terminal boxed regions outline mature PA1 chain-b peptide sequence in Fabaceae albumins, and the mature sequence of cyclotide Cter M. C-terminal boxed regions outline predicted mature PA1 chain-a peptide sequence.

FIG. 19A-19F provides SignalP analysis of Cter M, kalata B1 and selected albumin-1 precursors from Fabaceae. Panel A-SignalP (Bendtsen, J. D., et al., (2004), J. Mol. Biol. 340, 783-795) analysis of Cter M precursor protein (partial sequence shown as SEQ ID NO:104) predicts signal peptidase cleavage at the proto-N-terminus of the mature cyclotide sequence, between signal peptide residues 24 and 25 (72.9% probability). Panel B-SignalP analysis of kalata B1 precursor protein (partial sequence shown as SEQ ID NO:105) predicts signal peptidase cleavage between precursor protein residues 22 and 23 (82.5% probability). As in all previously characterized cyclotide genes, a pro-region and an N-terminal repeat region are encoded prior to the start of the first cyclotide domain. Panels C through F-Respective SignalP analyses of albumin-1 precursor proteins from Pisum sativum, Medicago truncatula, Phaseolus vulgaris, and Glycine max (partial sequences shown as SEQ ID NOS:106-109, respectively) predict signal peptidase cleavage at the proto-N-termini of mature PA1b peptide sequences. Cleavages are predicted between residues 26 and 27 (53.0%), 22 and 23 (51.1%), 27 and 28 (69.7%), and 19 and 20 (98.6%) respectively.

FIG. 20 shows that Cter M is resistant to proteolysis by trypsin and chymotrypsin. Leaf extract showing native Cter M at m/z 3058.3 (A, C) was subjected to trypsin (B) and chymotrypsin (D) digestion with no observed hydrolysis. The reduced and alkylated peptide, m/z 3407.6 (E, G, I) underwent proteolytic cleavage by trypsin (F) and chymotrypsin (H, J). As there is only a single tryptic site, the trypsin digestion product is observed at m/z 3424.6, whereas there were three chymotryptic sites resulting in the formation of major products at m/z 1450.7, 1511.7 and 1931.8 corresponding to KNGLPTCGETCL (SEQ ID NO:129), VPDCSCSWPICM (SEQ ID NO::130) and KNGLPTCGETCLGTCY (SEQ ID NO:131) respectively.

FIG. 21 provides a sensorgram for Cter M binding to POPC vesicles (A) immobilized on the chip surface. The peptide samples were injected from 0 to 180 s otherwise buffer was flowing. The sensorgrams were referenced using a blank flow cell with no peptide. Equilibrium binding curves for Cter M and kB1 binding to immobilized lipid vesicles (B). Fit to the single site binding model is shown as a solid line.

FIG. 22 shows analytical HPLC and mass spectrometric analysis showing that native and synthetic Cter M are identical. (A) Native Cter M; (B) Synthetic Cter M; and (C) Co-elution of Native and Synthetic Cter M. MALDI-TOF mass spectra of (D) Native Cter M extracted from Clitoria ternatea leaf material and (E) Synthetic Cter M.

DEFINITIONS

As used herein, the term “molecular framework” refers to a proteinaceous molecule having a defined three-dimensional structure. This defined three-dimensional structure comprises loops of amino acid residues and other elements of molecular structure held in defined orientation with respect to each other. The molecular framework itself may exhibit a particularly useful property such as having anti-pathogen activities against viruses, microorganisms, fungi, yeast, arachnids and insects or it may confer useful therapeutic properties in plants or animals. Furthermore, it may provide the framework for inserting one or more amino acids or amino acid sequences capable of conferring a desired biological effect. Insertion of one or more amino acid residues or sequences may occur on a beta-turn or within a loop. The molecular framework may also be presented in a linear form as a substrate for cyclization. Alternatively, a cyclic molecule may be derivatized into a linear form which itself may have useful properties or it may act as an agonist or antagonist of such properties.

The sequence of amino acids forming the backbone of the molecular framework may be naturally occurring amino acid residues or chemical analogues thereof. Chemical analogues of amino acid residues include non-naturally occurring amino acids. Examples of non-naturally occurring amino acids are shown in Table 3.

By way of example, when a molecular framework in the form of a cyclic polypeptide is isolated and purified from a biological source, such as a plant, the molecule generally comprises naturally occurring amino acid residues. However, the present invention extends to derivatives of such a molecular framework resulting from the insertion or substitution of non-naturally occurring amino acid residues or chemical analogues of amino acid residues. Alternatively, a single and/or a heterologous sequence of naturally occurring amino acid residues may be inserted or substituted into the molecular framework to confer desired properties on the molecule.

As used herein, the term “cyclic backbone” refers to a molecule comprising a sequence of amino acid residues or analogues thereof without free amino and carboxy termini. Preferably, the linkage between all amino acids in the cyclic backbone is via amide (peptide) bonds, but other chemical linkers are also possible. The cyclic backbone of the molecular framework of the present invention comprises sufficient disulfide bonds, or chemical equivalents thereof, to confer a knotted topology on the three-dimensional structure of the cyclic backbone.

In some embodiments, a cyclic backbone comprises a structure referred to herein as a “cystine knot”. A cystine knot occurs when a disulfide bond passes through a closed cyclic loop formed by two other disulfide bonds and the amino acids in the backbone. Such a cystine knot is referred to herein as a “cyclic cystine knot” or “CCK”. However, reference herein to a “cyclic cystine knot” or a “CCK” includes reference to structural equivalents thereof which provide similar constraints to the three-dimensional structure of the cyclic backbone. For example, appropriate turns and loops in the cyclic backbone may also be achieved by engineering suitable covalent bonds or other forms of molecular associations. All such modifications to the cyclic backbone which result in retention of the three-dimensional knotted topology conferred by the cyclic cystine knot are encompassed by the present invention. Furthermore, although a cyclic cystine knot is characterized by a knot formed by three disulfide bonds, the present invention extends to molecules comprising only two disulfide bonds. In such a case, the molecular framework may need to be further stabilized using other means or the molecular framework may retain suitable activity despite a change in three-dimensional structure caused by the absence of a third disulfide bond.

Cyclic backbones may comprise more than three disulfide bonds such as those occurring in a double or multiple cystine knot arrangement or in a single cystine knot arrangement supplemented by one or two additional disulfide bonds.

The term “cyclic cystine knot” and “CCK” and “cyclotide” are used interchangeably and encompass natural cystine knot peptides, as well as cystine knot peptides comprising modified amino acids, substituted loop sequences, grafted peptides, and other modifications. The terms “knot” and “cystine knot” are not to be limited by any mathematical or geometrical definition of the term “knot”. The knots contemplated by the present invention are referred to as such due to their similarity to a mathematical knot and/or by virtue of the intertwined features of the folded molecule.

The present invention provides, therefore, genes and expression systems encoding a molecular framework comprising a sequence of amino acids or analogues thereof forming a cyclic backbone and wherein said cyclic backbone comprises a cystine knot or its chemical or structural equivalent which confers a knotted topology on the three-dimensional structure of said cyclic backbone.

Accordingly, one aspect of the present invention contemplates an isolated nucleic acid molecule encoding a molecular framework comprising a sequence of amino acids forming a cyclic backbone wherein the cyclic backbone comprises sufficient disulfide bonds or chemical equivalents hereof to confer knotted topology on the molecular framework or part thereof wherein said cyclic backbone comprises the structure:—

wherein C is cysteine; each of (X_(1 . . .) X_(a)), (X^(I) _(1 . . .) X^(I) _(b)), (X^(II) _(1 . . .) X^(II) _(c)), (X^(III) _(1 . . .) X^(III) _(d)), (X^(IV) _(1 . . .) X^(IV) _(e)), (X^(V) _(1 . . .) X^(V) _(f)) represents one or more amino acid residues, wherein each one or more amino acid residues within or between the cysteine residues may be the same or different; and wherein a, b, c, d, e and f represent the number of amino acid residues in each respective sequence. In some embodiments, a, b, c, d, e and f may range from 1 to about 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

In certain preferred embodiments, the cyclic backbone of the present invention comprises the structure:

wherein a is about 6, b is about 5, c is about 3, d is about 1 or 2, e is about 5 and f is about 8; or an analogue of said sequence.

The molecular framework of the present invention is also referred to herein as a “cyclotide”. A cyclotide is regarded as being equivalent to a molecular framework as herein described and, in its most preferred embodiment, comprises a cyclic cystine knot motif defined by a cyclic backbone, at least two but preferably at least three disulfide bonds and associated beta strands in a particular knotted topology. The knotted topology involves an embedded ring formed by at least two disulfide bonds and their connecting backbone segments being threaded by a third disulfide bond. As stated above, however, a disulfide bond may be replaced or substituted by another form of bonding such as a covalent bond.

Each amino acid has a carboxyl group and an amine group, and amino acids link to one another to form a chain by joining the amine group of one amino acid to the carboxyl group of the next. Thus, linear polypeptide chains generally have an end with an unbound carboxyl group, the C-terminus, and an end with an amine group, the N-terminus. The convention for writing polypeptide sequences is to put the N-terminus on the left and write the sequence from N- to C-terminus. Sequences with longer or non-linear (e.g., cyclized) polypeptide that do not have unbound termini can nonetheless be directionally oriented by reference to the direction of the N and C groups on internal amino acid residues. For example, the amino acid in an internal region that would have a carboxyl group if on a terminus may be referred to as the C-terminal end of the internal sequence. The N and C designations also are used to indicate directionality on a polypeptide strand. For example, a first region of a polypeptide sequence that is attached by its C-terminal residue to the N-terminal residue of a second region of the same polypeptide may be referred to as being in the N or N-terminal direction from the second region. Conversely, the second region is in the C or C-terminal direction from the first region.

As used herein, the term “adjacent” as used in reference to amino acids or peptide regions refers to residues or regions that are contiguous or are immediately next to each other, e.g., in a polypeptide chain, with no intervening residues.

The terms “peptide” and “polypeptide” are used interchangeably herein to refer to a chain comprising a plurality amino acid residues connected by peptide bond(s). “Residue” as used in reference to an amino acid refers to an individual amino acid in a polypeptide chain.

As used herein, the term “graft” or “grafted” as used in reference to a peptide sequence used to modify a framework molecule, refers to the integration of a heterologous sequence of amino acids (a “heterologous peptide”) into the polypeptide strand at one or more positions on a framework molecule. For example, one or more loops of a CCK molecule may be made to comprise a heterologous sequence of amino acids in addition to, or as a full or partial replacement for a normal or native loop sequence. Grafting of a peptide into a CCK framework molecule need not be done after the proteinaceous framework molecule has been produced. In certain preferred embodiments, a peptide sequence, e.g., a bioactive peptide, is grafted into a framework proteinaceous molecule by creation of a nucleic acid molecule comprising a nucleotide sequence that encodes the framework CCK molecule along with the grafted peptide amino acid sequence.

In addition to the grafts described above, the present invention encompasses a range of amino acid substitutions, additions and/or insertions to the amino acid sequence of the molecular framework. Substitutions encompass amino acid alterations in which an amino acid is replaced with a different naturally-occurring or a non-conventional amino acid residue. Such substitutions may be classified as “conservative”, in which case an amino acid residue contained in a polypeptide is replaced with another naturally-occurring amino acid of similar character either in relation to polarity, side chain functionality, or size, for example, Ser

Thr

Pro

Hyp

Gly

Ala, Val

Ile

Leu, His

Lys

Arg, Asn

Gln

Asp

Glu or Phe

Trp

Tyr. It is to be understood that some nonconventional amino acids may also be suitable replacements for the naturally occurring amino acids. For example, ornithine, homoarginine and dimethyllysine are related to His, Arg and Lys.

Substitutions encompassed by the present invention may also be “non-conservative”, in which an amino acid residue which is present in a polypeptide is substituted with an amino acid having different properties, such as a naturally-occurring amino acid from a different group (e.g. substituting a charged or hydrophobic amino acid with alanine), or alternatively, in which a naturally-occurring amino acid is substituted with a nonconventional amino acid.

Amino acid substitutions are typically of single residues, but may be of multiple residues, either clustered or dispersed. Amino acids of the cyclic peptide backbone are preferably conservative in order to maintain the three-dimensional structure in a form functionally similar to the cyclic peptide before derivatization. Substitutions of amino acid residues in the cyclic peptide to introduce or otherwise graft heterologous sequences onto the backbone need not be conservative.

Additions encompass the addition of one or more naturally occurring or non-conventional amino acid residues. Deletion encompasses the deletion of one or more amino acid residues.

The present invention also includes molecules in which one or more of the amino acids has undergone side chain modifications. Examples of side chain modifications contemplated by the present invention include modifications of amino groups such as by reductive alkylation by reaction with an aldehyde followed by reduction with NaBH₄; amidination with methylacetimidate; acylation with acetic anhydride; carbamoylation of amino groups with cyanate; trinitrobenzylation of amino groups with 2,4,6-trinitrobenzene sulphonic acid (TNBS); acylation of amino groups with succinic anhydride and tetrahydrophthalic anhydride; and pyridoxylation oflysine with pyridoxal-5-phosphate followed by reduction with NaBH₄.

The guanidine group of arginine residues may be modified by the formation of heterocyclic condensation products with reagents such as 2,3-butanedione, phenylglyoxal and glyoxal.

The carboxyl group may be modified by carbodiimide activation via O-acylisourea formation followed by subsequent derivitization, for example, to a corresponding amide.

Sulfhydryl groups may be modified by methods such as carboxymethylation with iodoacetic acid or iodoacetamide; performic acid oxidation to cysteic acid; formation of mixed disulfides with other thiol compounds; reaction with maleimide, maleic anhydride or other substituted maleimide; formation of mercurial derivatives using 4-chloromercuribenzoate, 4-chloromercuriphenylsulphonic acid, phenylmercury chloride, 2-chloromercuri-4-nitrophenol and other mercurials; carbamoylation with cyanate at alkaline pH. Any modification of cysteine residues preferably does not affect the ability of the peptide to form the necessary disulfide bonds. It is also possible to replace the sulfhydryl groups of cysteine with selenium or tellurium equivalents such that the peptide forms a diselenide or ditelluride bond in place of one or more of the disulfide bonds.

Tryptophan residues may be modified by, for example, oxidation with N-bromosuccinimide or alkylation of the indole ring with 2-hydroxy-5-nitrobenzyl bromide or sulphenyl halides. Tyrosine residues on the other hand, may be altered by nitration with tetranitromethane to form a 3-nitrotyrosine derivative. Modification of the imidazole ring of a histidine residue may be accomplished by alkylation with iodoacetic acid derivatives or N-carbethoxylation with diethylpyrocarbonate. Proline residues may be modified by, for example, hydroxylation in the 4-position. Other modifications include succinimide derivatives of aspartic acid.

A list of some amino acids having modified side chains and other unnatural amino acids is shown in Table 3, below.

TABLE 3 Non-conventional amino acid Code Non-conventional amino acid Code α-aminobutyric acid Abu L-N-methylalanine Nmala α-amino-α-methylbutyrate Mgabu L-N-methylarginine Nmarg aminocyclopropane- Cpro L-N-methylasparagine Nmasn carboxylate L-N-methylaspartic acid Nmasp aminoisobutyric acid Aib L-N-methylcysteine Nmcys aminonorbornyl- Norb L-N-methylglutamine Nmgln carboxylate L-N-methylglutamic acid Nmglu α-aspartic acid Aaa β-aspartic acid Baa cyclohexylalanine Chexa L-Nmethylhistidine Nmhis cyclopentylalanine Cpen L-N-methylisolleucine Nmile D-alanine Dal L-N-methylleucine Nmleu D-arginine Darg L-N-methyllysine Nmlys D-aspartic acid Dasp L-N-methylmethionine Nmmet D-cysteine Dcys L-N-methylnorleucine Nmnle D-glutamine Dgln L-N-methylnorvaline Nmnva D-glutamic acid Dglu L-N-methylornithine Nmorn D-histidine Dhis L-N-methylphenylalanine Nmphe D-isoleucine Dile L-N-methylproline Nmpro D-leucine Dleu L-N-methylserine Nmser D-lysine Dlys L-N-methylthreonine Nmthr D-methionine Dmet L-N-methyltryptophan Nmtrp D-ornithine Dorn L-N-methyltyrosine Nmtyr D-phenylalanine Dphe L-N-methylvaline Nmval D-proline Dpro L-N-methylethylglycine Nmetg D-serine Dser L-N-methyl-t-butylglycine Nmtbug D-threonine Dthr L-norleucine Nle D-tryptophan Dtrp L-norvaline Nva D-tyrosine Dtyr α-methyl-aminoisobutyrate Maib D-valine Dval α-methyl-γ-aminobutyrate Mgabu D-α-methylalanine Dmala α-methylcyclohexylalanine Mchexa D-α-methylarginine Dmarg α-methylcyclopentylalanine Mcpen D-α-methylasparagine Dmasn α-methyl-α-napthylalanine Manap D-α-methylaspartate Dmasp α-methylpenicillamine Mpen D-α-methylcysteine Dmcys N-(4-aminobutyl)glycine Nglu D-α-methylglutamine Dmgln N-(2-aminoethyl)glycine Naeg D-α-methylhistidine Dmhis N-(3-aminopropyl)glycine Norn D-α-methylisoleucine Dmile N-amino-α-methylbutyrate Nmaabu D-α-methylleucine Dmleu α-napthylalanine Anap D-α-methyllysine Dmlys N-benzylglycine Nphe D-α-methylmethionine Dmmet N-(2-carbamylethyl)glycine Ngln D-α-methylornithine Dmorn N-(carbamylmethyl)glycine Nasn D-α-methylphenylalanine Dmphe N-(2-carboxyethyl)glycine Nglu D-α-methylproline Dmpro N-(carboxymethyl)glycine Nasp D-α-methylserine Dmser N-cyclobutylglycine Ncbut D-α-methylthreonine Dmthr N-cycloheptylglycine Nchep D-α-methyltryptophan Dmtrp N-cyclohexylglycine Nchex D-α-methyltyrosine Dmty N-cyclodecylglycine Ncdec D-α-methylvaline Dmval N-cyclododeclglycine Ncdod D-N-methylalanine Dnmala N-cyclooctylglycine Ncoct D-N-methylarginine Dnmarg N-cyclopropylglycine Ncpro D-N-methylasparagine Dnmasn N-cycloundecylglycine Ncund D-N-methylasparatate Dnmasp N-(2,2-diphenylethyl)glycine Nbhm D-N-methylcysteine Dnmcys N-(3,3-diphenylpropyl)glycine Nbhe D-N-methylglutamine Dnmgln N-(3-guanidinopropyl)glycine Narg D-N-methylglutamate Dnmglu N-(1-hydroxyethy)glycine Nthr D-N-methylhistidine Dnmhis N-(hydroxyethy))glycine Nser D-N-methylisoleucine Dnmile N-(imidazolylethyl))glycine Nhis D-N-methylleucine Dnmleu N-(3-indolylyethyl)glycine Nhtrp D-N-methyllysine Dnmlys N-methyl-γ-aminobutyrate Nmgabu N-methylcyclohexylalanine Nmchexa D-N-methylmethionine Dnmmet D-N-methylornithine Dnmorn N-methylcyclopentylalanine Nmcpen N-methylglycine Nala D-N-methylphenylalanine Dnmphe N-methylaminoisobutyrate Nmaib D-N-methylproline Dnmpro N-(1-methylpropyl)glycine Nile D-N-methylserine Dnmser N-(2-methylpropyl)glycine Nleu D-N-methylthreonine Dnmthr D-N-methyltryptophan Dnmtrp N-(1-methylethyl)glycine Nval D-N-methyltyrosine Dnmtyr N-methyla-napthylalanine Nmanap D-N-methylvaline Dnmval N-methylpenicillamine Nmpen γ-aminobutyric acid Gabu N-(p-hydroxyphenyl)glycine Nhtyr L-t-butylglycine Tbug N-(thiomethyl)glycine Ncys L-ethylglycine Etg penicillamine Pen L-homophenylalanine Hphe L-α-methylalanine Mala L-α-methylarginine Marg L-α-methylasparagine Masn L-α-methylaspartate Masp L-α-methyl-t-butylglycine Mtbug L-α-methylcysteine Mcys L-methylethylglycine Metg L-α-methylglutamine Mgln L-α-methylglutamate Mglu L-α-methylhistidine Mhis L-α-methylhomophenylalanine Mhphe L-α-methylisoleucine Mile N-(2-methylthioethyl)glycine Nmet L-α-methylleucine Mleu L-α-methyllysine Mlys L-α-methylmethionine Mmet L-α-methylnorleucine Mnle L-α-methylnorvaline Mnva L-α-methylornithine Morn L-α-methylphenylalanine Mphe L-α-methylproline Mpro L-α-methylserine Mser L-α-methylthreonine Mthr L-α-methyltryptophan Mtrp L-α-methyltyrosine Mtyr L-α-methylvaline Mval L-N-methylhomophenylalanine Nmhphe N-(N-(2,2-diphenylethyl) Nnbhm N-(N-(3,3-diphenylpropyl) Nnbhe carbamylmethyl)glycine carbamylmethyl)glycine 1-carboxy-1-(2,2-diphenyl- Nmbc ethylamino)cyclopropane

As used herein, the terms “isolated” or “substantially isolated” as used in reference to molecules, e.g., either nucleic or amino acid, refers to molecules that are removed from their natural environment, purified or separated, and are at least partially free, preferably 50% free, more preferably 75% free, and most preferably 90% free from other components with which they are naturally associated. An “isolated” molecule that is separated from components with which it is associated in nature need not be isolated from other materials, and may be, for example, combined with other components e.g., heterologous host cell components, reaction components and the like.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides cyclotides isolated from plants in the Fabaceae family of plants. In some embodiments, the present invention further provides isolated nucleic acids configured for expression in plants of the Fabaceae family and encoding a molecular framework comprising a sequence of amino acids or analogues thereof forming a cyclic backbone, wherein said cyclic backbone comprises sufficient disulfide bonds, or chemical equivalents thereof, to confer a knotted topology on the three-dimensional structure of said cyclic backbone. In still other embodiments, the present invention provides isolated nucleic acids configured for expression in plants of the Fabaceae family and encoding a molecular framework as described above and containing a heterologous grafted peptide. In preferred embodiments, the grafted peptide confers a bioactivity on said molecular framework molecule.

The Fabaceae (legume) plant family is the third largest family of plants on earth comprising 18,000 species, many of which, e.g., peas and beans, are centrally involved in human nutrition. The discovery of cyclotides in the Fabaceae family broadens interest in this family of molecules because it facilitates the possibility of expressing genetically modified cyclotide sequences in crop plants from the Fabaceae. In addition to their importance as crop plants, multiple members of the Fabaceae family of plants are amenable to transfection. Modification of these plants to express foreign or engineered cyclotides finds a number of applications, including conferring insect resistance traits on the host plants themselves. In some embodiments, the host plants may be used to manufacture cyclotides having, for example, pharmaceutical attributes. It is envisioned that expressed cyclotides may be purified from the host plants or, in some embodiments, plant materials having beneficial pharmaceutical attributes may be used directly, e.g., in foods or food supplements or in the preparation of topical treatments, etc.

The present invention provides a genetic system for the expression of cyclotides in the Fabaceae plant family. We provide herein nucleic acid sequences encoding cyclotides from the Fabaceae plant family and show that the corresponding peptide is ultra-stable and insecticidal like other cyclotides, but has an unexpected biosynthetic origin in that it is embedded within an albumin precursor sequence.

In some embodiments, the present invention comprises isolated nucleic acids configured to encode Fabaceae-derived cyclotides comprising grafted heterologous peptides. The heterologous amino acids inserted or substituted in the molecular framework have the capacity to confer a range of activities and biological properties to the molecule including modulating calcium channel-binding, which is useful in the treatment of pain or a stroke, C5a binding, useful as an anti-inflammatory agent, proteinase inhibitor activity in plants or animals, antibiotic activity, anti-HIV activity, anti-microbial activity, anti-fungal activity, anti-viral activity, anthelmintic activity, cytokine binding ability and blood clot inhibition and plant pathogen activity (e.g., insecticidal activity) amongst other properties. The molecule may be a modulator in the sense that it may facilitate the activity or inhibit the activity. Accordingly, the molecule may act as an agonist or antagonist. Furthermore, the heterologous amino acids may form a sequence which may be readily cleaved to form a linear molecule, or to activate a peptide that requires cleavage by a proteinase for activation.

Peptides having defined biological activity, including peptides containing about 30 or fewer amino acid residues, particularly suitable for grafting, are well known. At this time, tens of thousands of peptides of this kind have been described in the scientific literature and have been recorded in peptide databases. See, e.g., Peptide Atlas published on the worldwide web at peptideatlas.org, at or PepBank, maintained online by Massachusetts General Hospital, Harvard University, Cambridge, Mass., each incorporated by reference herein. In addition, screening of peptides of unknown sequence to identify peptides having defined biological activities, including random combinatorial libraries containing millions of peptides, is conventional in the art and requires no knowledge of what amino acid sequence or peptide structure would predictably result in the desired activity. See, for example, Cortese, et al., (1995) Curr. Opin. Biotech. 6:73-80, incorporated by reference herein, which discusses of the phage display method of screening random combinatorial peptide libraries. In some embodiments, the present invention comprises selecting an amino acid sequence of a peptide having a defined biological activity, preparing protein molecules having cyclic cystine knot backbones in which one or more of the loops contains the amino acid sequence of the peptide, and screening the prepared proteins using an assay for the defined biological activity so as to identify a CCK protein having the defined biological activity. In some embodiments, the peptide has a sequence of about 30 or fewer amino acids. In certain embodiments, peptides are grafted into one or more of loops 1, 2, 3, 4, 5, and/or 6. In certain preferred embodiments, peptides are grafted into one or more of loops 1, 2, 3, 5, and/or 6.

While some embodiments of CCK molecules contain loops comprising 1 to about 7 amino acids, it is known that cystine knot structures comprising six cysteines and three disulfide bonds can be formed with larger polypeptides. Larger polypeptides of this configuration have loop sizes from 1 up to 30 or more amino acid residues.

The molecular frameworks of the Fabaceae CCK molecules permit modifications to be made to the molecule while retaining the stable structural scaffold. Such modifications include, for example, different amino acid residues inserted or substituted anywhere in the molecule but preferably in one or more beta-turns and/or within a loop. The newly exposed amino acids, for example, may provide functional epitopes or activities not present in the molecular framework prior to modification. Alternatively, the newly exposed amino acids may enhance an activity already possessed by the molecular framework. A substitution or insertion may occur at a single location or at multiple locations. Furthermore, the molecular framework may be specifically selected to more readily facilitate substitution and/or insertion of amino acid sequences. Such modified forms of the molecular framework are proposed to have a range of useful properties including as therapeutic agents for animals and mammals (including humans) and plants. Therapeutic agents for plants include pest control agents. As stated above, the molecular framework has advantages in terms of increased stability relative to, for example, conventional peptide drugs. The increased stability includes resistance or less susceptibility to protease cleavage. Furthermore, the molecules may have a hydrophobic face which may benefit their interaction with membranes while still being highly water soluble.

Accordingly, another aspect of the present invention is directed to a Fabaceae molecular framework comprising a sequence of amino acids or analogues thereof forming a cyclic backbone and wherein said cyclic backbone comprises sufficient disulfide bonds or chemical equivalents thereof, to confer a knotted topology on the three-dimensional structure of said cyclic backbone and wherein at least one exposed amino acid residue such as on one or more beta turns and/or within one or more loops, is inserted or substituted relative to the naturally occurring amino acid sequence.

Even more particularly, the present invention contemplates a Fabaceae molecular framework comprising a sequence of amino acids or analogues thereof forming a cyclic backbone and wherein said cyclic backbone comprises a cystine knot or its chemical or structural equivalent which confers a knotted topology on the three-dimensional structure of said cyclic backbone and wherein at least one exposed amino acid residue such as on one or more beta turns and/or within one or more loops is inserted or substituted relative to the naturally occurring amino acid sequence.

More particularly, the present invention is directed to a Fabaceae molecular framework comprising a sequence of amino acids or analogues thereof forming a cyclic cystine knot motif defined by a cyclic backbone, at least three disulfide bonds and associated beta stands in a defined knotted topology and wherein at least one exposed amino acid residue such as on one or more beta turns or within one or more loops is inserted or substituted relative to the naturally occurring amino acid sequence.

It is contemplated that in some embodiments, a cyclic cystine knot is formed by expression of a linear precursor molecule comprising the cystine knot motif in a host cell that comprises a system of one or more enzymes for processing a precursor form of a cystine knot polypeptide to produce a cyclic cystine knot polypeptide. In other embodiments, a cystine knot polypeptide is cyclized in vitro. In some embodiments, in vitro processing is carried out enzymatically, e.g., using an isolated enzymatic processing system e.g., from a cyclotide-forming plant species, while in some embodiments, in vitro cyclizing is done by chemical treatment, e.g. in ammonium bicarbonate with triscarboxyethylphosphine (TCEP), as described, e.g., by Craik, et al., US Patent Publication 2003/0158096, which is incorporated by reference herein it its entirety for all purposes.

Although the inserted or substituted amino acid is preferably an exposed amino acid on a beta turn, the present invention contemplates an inserted or substituted amino acid anywhere on the molecule.

The inserted or substituted amino acid residues may be a single residue or may be a linear sequence of from about two residues to about 60 residues, preferably from about two to about 30 residues, and even more preferably, from about 2 residues to about 10 residues. The insertion or substitution may occur at a single location or at multiple locations. The latter includes the insertion of non-contiguous amino acid sequences. Furthermore, different amino acid molecules may be inserted/substituted at different sites on the molecule. This is particularly useful in the preparation of multivalent or multifunctional molecules.

One example of a class of larger cystine knotted polypeptides is the Vascular Endothelial Growth Factors (VEGFs), described in the reference by K. Suto, et al., (2005) J. Biol. Chem. 290:2126. For example, VEGF-A₁₆₅ is composed of 165 residues (p 2126, col 2). Suto et al., provides a sequence comparison of two VEGF-related proteins called vammin (110 residues) and VR-1 (109 residues) to VEGF-A₁₆₅ and PlGF (Placental Growth Factor). As shown in FIG. 2 of Suto et al., each of these cystine knot polypeptides contains loops of up to 33 amino acid residues.

Inclusion of loops of 30 or more amino acids is not limited to the VEGF polypeptides. See, e.g., Table 2, which comprises about 1500 naturally occurring polypeptides containing cystine knot motifs. Each of the polypeptides listed has been reported to contain a cystine knot comprising six cysteine residues and at least five loops, while circular molecules have a sixth loop. The polypeptides are identified by database identifiers listed in column 1. The table provides the complete list of polypeptides reciting the sizes of each of loops in its cystine knot motif, and shows the amino acid sequences of each of the loops in its cystine knot motif. The table of cystine knot polypeptide sequences provided herewith shows that cystine knot structures can readily accommodate 30 or more amino acids in one or several loops.

Identification of Cyclotides in C. ternatea.

Clitoria ternatea, an ornamental perennial climber also known as the Butterfly pea, is a member of plant family Fabaceae, originally from Africa but now also distributed among equatorial Asiatic countries and the Americas. Preparations of C. ternatea are utilized in a variety of indigenous medicines throughout these regions, with anecdotal evidence of their use in the traditional medicines of the Philippines, Cuba and Indo-China to promote uterine contractions and expedite childbirth (Fantz, P. R. (1991) Econ. Bot. 45, 511-520; Mukherjee, P. K., et al. (2008) J. Ethnopharmacol. 120, 291-301).

Initial screening of crude seed extracts of C. ternatea revealed the presence of proteins with masses in the range 2500-4000 Da, consistent with those of known cyclotides. Following preparative RP-HPLC of the crude extract, the putative cyclotides were detected in late-eluting fractions via MALDI-TOF MS (FIG. 2A), and the masses of 12 of these putative cyclotides are reported in Table 1. In accordance with established diagnostic methodology for cyclotides (Gruber, supra), purified peptides were lyophilized, reduced and carbamidomethylated, and re-analyzed via MALDI-TOF MS. Mass increases of 348 Da, were observed following this process (FIG. 2B), indicating the presence of three intramolecular disulfide bonds in the corresponding proteins. Thus, the 12 peptides complied with all three diagnostic criteria previously identified for cyclotides (Gruber, supra), of mass profile, hydrophobicity profile, and disulfide content.

Seven cyclotide sequences were also identified from C. ternatea leaf and flower of which one, Cter A, was common to seed. Cter M was tested for insecticidal activity and was determined to have insecticidal activity against the cotton budworm Helicoverpa armigera and anthelmintic activity against Haemonchus contortus. Cter M also binds to PE membranes, suggesting its activity is modulated by membrane disruption. Sequences of the leaf and flower cyclotides, along with the seed cyclotides, are shown in FIG. 9.

Tandem MS Enables the Differentiation of Cyclotides from Linear Peptides.

There are several examples of linear proteins, including knottins and also some defensins, which are of similar size to cyclotides, possess three disulfide bonds, and display hydrophobic properties. Therefore, we sought to extend the diagnostic criteria for the detection of cyclotides by including an additional step to distinguish between peptides with cyclic or linear backbones. This additional step is illustrated for the putative cyclotide from C. ternatea seed extract, Cter A, with a ‘native’ mass of 3267.3 Da that increases by 348 Da after reduction and carbamidomethylation and a further 18 Da after enzymatic digestion of the peptide backbone with endoproteinase Glu-C (FIG. 3). The determination of peptide sequence via tandem MS relies in part upon the ability of the N- and C-termini to retain charge. The absence of termini in cyclotides, brought about by their macrocyclic peptide backbone, therefore prevents their efficient fragmentation in tandem MS analyses, either as fully folded CCK-containing ‘native’ proteins or as reduced and alkylated cyclic proteins, as illustrated for Cter A in panels A and B of FIG. 3, respectively. Only after enzymatic cleavage of reduced (or reduced and alkylated) C. ternatea peptides into their linear forms were the various fragment ions detected during tandem MS analyses (FIG. 3C). Hence, we propose that the characteristic lack of fragmentation observed in tandem MS analyses of reduced and/or reduced and alkylated cyclotides is a suitable determinant of their cyclic nature, and should be added to previously proposed criteria (Gruber, supra) as an indicator for the presence of cyclotides in a given plant.

In combination, the newly defined criteria proposed here for the positive identification of cyclotides are late-eluting properties via RP-HPLC, a mass of 2500 to 4000 Da, an increase in mass of 348 Da following reduction and alkylation with iodoacetamide, and inefficient fragmentation in MS/MS analyses of ‘native’ or reduced and alkylated forms. Although yet to be described from plants, cyclic peptides with three intramolecular disulfide bonds not forming a cystine knot arrangement, similar to rhesus θ-defensin-1 (Tang, Y.-Q., et al., (1999) Science 286, 498-502), could also meet these criteria. However, judging from the size and hydrophobicity of described O-defensins, false positives are unlikely.

De Novo Sequencing of Cyclotides.

To illustrate the sequencing of the new cyclotides the step-by-step MS/MS analysis of Cter B is shown in FIG. 4. The linearized peptide resulting from endoproteinase Glu-C digestion of the reduced form of Cter B was analyzed via nanospray MS/MS. De novo sequencing yielded a tentative identification of SCVWIPCTVTALLGCSCKDKVCYLNGVPCAE (SEQ ID NO:1). As indicated in FIG. 4B, sequence ion coverage permitted definitive assignment of the sequence near the termini of the peptide, but presented incomplete evidence for sequence close to the middle of the peptide, a feature observed in the analyses of many full-length linearized cyclotides. Combined trypsin and endoproteinase Glu-C digestion of reduced Cter B produced peptide fragments with complementary molecular weights of 1882.6 Da and 1409.4 Da. Complete sequence coverage for both precursors was attained in tandem MS analyses (FIGS. 4C and 4D), verifying the initial sequence assignment for the full-length linearized cyclotide. Using this approach, 12 novel cyclotides from C. ternatea were sequenced (see Table 1 in Example 1). Amino acid analyses were conducted to confirm the MS/MS determined sequences and to discriminate between Ile and Leu for a representative set of cyclotides, including Cter A, Cter B and C, Cter D and E, Cter F, and Cter G and Cter H.

Cyclotides are classified mainly into two subfamilies, Möbius or bracelet, based upon the presence or absence of a cis-Pro amide bond in loop 5. Cyclotides belonging to the bracelet subfamily are the most widely represented in the literature, at approximately three-fold greater incidence than cyclotides belonging to the Möbius subfamily. Consistent with this prominence, the sequences discovered in the current study, all belong to the bracelet subfamily. However, several of them have unusual residues at key processing sites, making them of interest for understanding processing mechanisms of cyclotides.

An efficient way in which to describe and compare the features of cyclotides is by referring to the inter-cysteine loops, illustrated in FIG. 5 as an amino acid incidence plot for the 12 new sequences in sequence logo format (Crooks, G. E., et al., (2004), Genome Res. 14, 1188-1190). Most of the new cyclotides comprised combinations of known loops from previously characterized cyclotides, or novel loops with conservative amino acid substitutions. As a result, the majority of sequences displayed significant homology to known cyclotides. According to the sequence logo plot, the greatest variation in loop size and/or composition are in loops 3 and 6, consistent with data for all published cyclotide sequences as assessed using the ‘cyclotide loop view’ tool within Cybase (Kaas, Q., and Craik, D. J. (2010), Peptide Sci. 94, 584-591).

Biochemical Properties, of Novel Cyclotides.

Since the initial discovery of the insecticidal activity of cyclotides (Jennings, C., et al., (2001) Proc. Natl. Acad. Sci. USA 98, 10614-10619), several studies have demonstrated that this and other bioactivities are mediated through interactions with membranes (Barbeta, B. L., et al., (2008), Proc. Natl. Acad. Sci. USA 105:1221-1225). An important physicochemical feature of cyclotides, with regard to membrane interaction, is a surface-exposed patch of hydrophobic residues. This surface-exposure presumably results from the exclusion of hydrophobic amino acids from the core of cyclotides owing to the presence of the CCK motif. In addition to the importance of defined hydrophobic moieties in potentiating cyclotide-membrane interactions, clusters of charged residues have been demonstrated as determinants of hemolytic, insecticidal and anthelmintic activity. In particular, the hemolytic and anthelmintic properties of cyclotide variants correlate with these important structural features (Colgrave, M. L., et al., (2008) ChemBioChem 9, 1939-1945), with the most bioactive bracelet cyclotides displaying hydrophobic residues in loops 2 and 3, and positively charged residues in loops 5 and 6.

Among the novel Cter cyclotides identified here, Cter A has the largest net positive charge (2+) with basic residues clustered in loops 5 and 6, similar to the cycloviolacin peptides derived from Viola odorata that have been shown to possess potent anthelmintic activity (Colgrave, M. L., et al., (2008) ChemBioChem 9, 1939-1945; and Colgrave, M. L., et al., (2009), Acta Trop. 109, 163-166). The remaining peptides are clustered into groups with net positive 1+ (Cter G and Cter I), neutral (Cter B, Cter F, Cter H, Cter J and Cter K) and those with net negative charge −1 (Cter C, Cter E and Cter L). The bioactivities of cyclotides are further influenced by the manner in which they self-associate in membranes, which in turn is reliant upon the display of hydrophilic moieties on a ‘bioactive face’ spatially distinct from the hydrophobic patches (Huang, Y. H., et al., (2009) J. Biol. Chem. 284, 20699-20707, Huang, et al., (2010) J. Biol. Chem.; DOI: 10.1074/jbc.M109.089854). The proposed ‘bioactive face’ is centred around a glutamic acid residue, an absolutely conserved feature among previously reported cyclotides. Consistent with previous findings, this glutamic acid is conserved among all novel cyclotides described in this study.

Detection of N and D Peptide Isomers.

Mass spectrometric analyses of a majority of isolated C. ternatea cyclotides generated peptide ions with ambiguous isotope patterns. The isotopic distributions of full-length linearized Cter B, as well as fragment peptides produced from dual enzyme digests of Cter B are shown in FIG. 6. As illustrated in panel A, the measured intensity of the monoisotopic peak at m/z 1092.4 relative to the rest of the isotopic envelope for full-length linearized Cter B is less than the theoretical intensity (indicated by dashed lines). Panel B demonstrates that the experimental and calculated isotopic distributions for the triply charged precursor at m/z 628.5 corresponding to the sequence SCVWIPCTVTALLGCSCK (SEQ ID NO:2) match closely, whereas the experimental and calculated isotopic distributions for the doubly charged precursor at m/z 705.7 (panel C) corresponding to the sequence DKVCYLNGVPCAE (SEQ ID NO:3) are clearly different. These mass spectral data indicate that multiple full-length cyclotide precursors are present in the sample, and that the variable isotopic distributions observed among the precursor ions are associated with the cyclotide fragment corresponding to m/z 705.7.

Subsequent tandem MS analysis of the m/z 705.7 fragment was conducted to determine the point of variation in the peptide sequence. Panel D shows the tandem MS spectrum of the m/z 705.7 precursor, with diagnostic sequence ions indicated in bold. In panel E the b6 (DKVCYL (SEQ ID NO:132), m/z 722.2) and y6 (GVPCAE (SEQ ID NO:133), m/z 575.1) ions exhibit typical isotopic distributions for their size, with the monoisotopic peak appearing as the most intense and with isotopic patterns matching closely with the theoretical patterns. The distributions for b7 (DKVCYLN (SEQ ID NO:134), m/z 836.3) and y7 (NGVPCAE (SEQ ID NO:135), m/z 689.1) ions, however, are skewed such that the most intense peak within their respective isotopic envelopes is that which normally corresponds to the monoisotopic peak of an analyte bearing a single ¹³C atom. The fact that the peptide fragments in question are too small for this to be the case, along with the abrupt deviations in isotopic distribution from adjacent sequence ions, suggests the co-existence of peptides with an Asn or Asp at position 7 within the m/z 705.7 fragment, i.e., DKVCYLNGVPCAE (SEQ ID NO:3) and DKVCYLDGVPCAE (SEQ ID NO:136), corresponding to position 31 in the sequence of Cter B shown in Table 1. Of the C. ternatea cyclotides listed in Table 1, five pairs of sequences appear to be related through dual-isotope patterns of this nature, i.e. Cter B and C; Cter D and E; Cter G and H; Cter I and J; and Cter K and L.

In the initial report detailing the discovery of cyclotides from Viola odorata (Craik, D. J., et al., (1999) J. Mol. Biol. 294, 1327-1336), the reported cyclotides, named cycloviolacins, all possessed an Asn in loop 6 corresponding to the C-terminus of linear precursor proteins. Subsequent examination of V. odorata using modified HPLC conditions (Ireland, D. C., et al., (2006) Biochem. J. 400, 1-12) uncovered a range of novel cyclotides. The novel peptides included cycloviolacin O19 and cycloviolacin O20, whose sequences are highly homologous to those of previously reported cyclotides cycloviolacin 08 and cycloviolacin O3, respectively. Cycloviolacin O19 and cycloviolacin O20 possess a loop 6 Asp, in the place of Asn, and were not reported in the earlier study (Craik, D. J., et al., (1999) J. Mol. Biol. 294, 1327-1336). The study by Ireland et al. therefore provided the first evidence for the existence of Asn and Asp C-terminal cyclotide isoforms in V. odorata, indicating that highly homologous cyclotides differing by a C-terminal Asn or Asp, or other single amino acid substitutions co-elute during standard HPLC separations. Given that most cyclotide separations reported in the literature have relied on these standard HPLC conditions, it is likely that in these studies, cyclotides with C-terminal Asn and Asp co-eluted, thus eluding analysis.

MS analysis demonstrates that Asn and Asp variants can be identified in a mixture through careful scrutiny of MS data. Furthermore, this study suggests that cyclotides with C-terminal Asp might be more common than previously reported, being missed in earlier MS analyses. The possibility also exists that cyclotides differing by 1 Da but whose sequences are homologous such as those that would result from the differential incorporation of Gln or Glu, or those that differ at a range of positions may co-elute.

N and D Peptide Isomers Exist Naturally in Planta.

Of the more than 150 cyclotides characterized previously, only four pairs share sequences otherwise identical to each other apart from Asn and Asp variation in loop 6, i.e., kalata B1 and B4, kalata B6 and B10, cycloviolacin O8 and O19, and cycloviolacin O3 and O20 (Kaas, Q., and Craik, D. J. (2010), Peptide Sci. 94, 584-591). Therefore, the high incidence of Asn and Asp variants warranted further examination to rule out deamidation as a possible cause of the synonymous sequences. Deamidation of Asn residues during sample workup is a commonly observed artefact in proteomic analyses, catalysed by exposure of the sample to elevated temperatures and basic pH (Wright, H. T. (1991), Crit. Rev. Biochem. Mol. Biol. 26, 1-52), typically during enzymatic cleavage, and occurring most frequently at Asn residues immediately N-terminal to Gly, as would be the case in these cyclic proteins. However, the isotopic distributions of ‘native’ cyclotides extracted from fresh plant material at low pH and not heated before MS analysis suggest that Asn and Asp cyclotide variants described, e.g., Cter B and C; Cter D and E; Cter G and H; Cter I and J; and Cter K and L, co-exist naturally. The existence of Cter A and Cter F, which do not display ‘Asn or Asp variability’ and which were isolated from the same starting material and processed in parallel supports the natural co-existence of Asn and Asp C-terminal cyclotide isoforms.

A recent study of ESTs from the cyclotide-producing plant O. affinis reports high relative expression of a protein with close homology to asparaginase, whose biological function is the conversion of asparagine to aspartic acid (Qin, Q., et al., (2010) BMC Genomics 11, DOI: 10.1186/1471-2164-11-111). With respect to pairs of cyclotides isolated from O. affinis differing only at the nascent C-terminus, the fact that only kalata B1 and kalata B6 (C-terminal Asn) genes have been found despite peptide evidence for kalata B1 and B4, and kalata B6 and B10 (each pair identical except for C-terminal Asn or Asp), led Qin et al. to suggest the alternative possibility that the ‘Asp’ peptides are a product of post-translational processing occurring in planta (Qin 2010, supra). A similar situation exists for related V. odorata peptides cycloviolacin O8 (C-terminal Asn) and cycloviolacin O19 (C-terminal Asp), with only the gene encoding the former cyclotide having been characterized (Dutton, J. L., et al., (2004) J. Biol. Chem. 279, 46858-46867). However, it remains to be determined whether the observed ‘Asn or Asp’ variable peptide pairs from O. affinis and V. odorata are a product of enzymatic post-translational processing, and further, whether a similar enzyme is involved in the biosynthesis of some metabolites with C-terminal Asp described from C. ternatea in this study.

Variable Residues in the Ligation Site Imply Catalytic Promiscuity.

Since the discovery of the first cyclotide-encoding gene, it has been evident that amino acids participating in cyclization are located in loop 6 of fully-formed cyclotides. Recent studies exploring the structural characteristics of cyclotide precursor sequences involved in their cyclization (Gillon, A. D., et al., (2008) Plant J. 53, 505-515; Saska, I., et al., (2007) J. Biol. Chem. 282, 29721-29728) emphasize the importance of tripeptide motifs (typically Gly-Leu-Pro or Ser-Leu-Pro or Ala-Leu-Pro) demarcating the cyclotide domain, and the positioning of an Asn or Asp residue immediately prior to the C-terminal tripeptide. In addition, these studies suggest that an as yet unidentified asparaginyl endopeptidase (AEP) is responsible for the ligation of cyclotide proto-termini as the final step of cyclotide biosynthesis.

Among the cyclotides encoded by the genes provided herein, Cter G and Cter H, and Cter K and Cter L contain novel amino acid sequences at their respective predicted sites of in planta cyclization. In the case of Cter G and Cter H, the loop 6 sequences ‘YNNGLP’ (SEQ ID NO:137) and ‘YNDGLP’ (SEQ ID NO:117) present the unique motifs Asn-Asn-Gly and Asn-Asp-Gly, which are noteworthy because they present two possible cyclization sites. The position of the peptide bond formed during cyclization of linear cyclotide precursors, as corroborated by gene sequencing efforts, is frequently observed at an Asn-Gly or the Asp-Gly junction. By itself, this information would suggest that the cyclization site in Cter H is Asp-Gly; however, the demonstrated cyclic nature of cycloviolacin O25 (Ireland, D. C., et al., (2006) Biochem. J. 400, 1-12), which presents a loop 6 sequence ‘YFNDIF’ (SEQ ID NO:138), tenders the alternative possibility that the cyclization reaction takes place between Asn-Asp. In the case of Cter K and Cter L, the loop 6 sequences are ‘YNHEP’ (SEQ ID NO:139) and ‘YDHEP’ (SEQ ID NO:140) with presumed novel cyclization sites Asn-His or Asp-His. Although there are other examples of cyclotides with a positively charged residue following Asp in the cyclization site (for example ‘YHDKIP’ (SEQ ID NO:141) in circulin D and circulin E) (Gustafson, K. R., et al., (2000) J. Nat. Prod. 63, 176-178), this is the first example with an acidic residue in place of the typically small hydrophobic residue (Ala, Ile, Leu or Val) at this position (second residue of mature cyclotide in presumed gene sequence). The existence of mature cyclic peptides with unusual residues within the N-terminal tripeptide motif (e.g. HEP in Cter K and Cter L) suggests greater flexibility in cyclotide processing mechanisms within C. ternatea than observed in other cyclotide-producing species. A recent study in which a modified cyclotide gene was expressed in transgenic non-cyclotide-containing plant species reported that mechanisms central to the processing of fully-formed cyclotides are sensitive to changes in N-terminal sequence. In particular, Ala mutations at Gly₁ or Leu₂ in kalata B1 genes were found to disrupt the formation of cyclic products (Gillon, A. D., et al., (2008) Plant J. 53, 505-515).

Legumain, an AEP with transpeptidation (peptide ligation) activity, first described in jack beans (Carrington, D. M., et al., (1985) Nature 313, 64-67, Min, W., and Jones, D. H. (1994) Nat. Struct. Biol. 1, 502-504), is of potential significance to the processing of cyclotides. In particular, the demonstrated flexibility of a Fabaceae legumain that cleaves at almost all Asn-Xaa bonds (Abe, Y., et al., (1993) J. Biol. Chem. 268, 3525-3529) and to a lesser extent Asp-Xaa bonds (Halfon, S., et al., (1998) FEBS Lett. 438, 114-118) may prove to be relevant in the biosynthesis of cyclotides from C. ternatea. Among the Fabaceae cyclotides investigated in the current study, those with non-typical sequence in loop 6 including ‘YNHEP’ (SEQ ID NO:139) or ‘YDHEP’ (SEQ ID NO:140) in Cter K and Cter L, and ‘YNNGIP’ (SEQ ID NO:141) or ‘YNDGIP’ (SEQ ID NO:142) in Cter G and Cter H were all observed as fully cyclized gene products.

Besides C. ternatea cyclotides possessing novel loop 6 sequences, there are a number of ‘orphan’ cyclotides whose loop 6 sequences appear incompatible with the typical activity of AEPs previously implicated in cyclotide bioprocessing. Apart from cycloviolacin O25, whose loop 6 sequence indicates the lack of typical putative N-terminal amino acids Gly, Ser or Ala in putative precursors, Chassalia parvifolia cyclotides circulin D and circulin E are distinct from other known cyclotides in that they have positively charged proto-N-termini, whereas circulin F does not have an Asn or Asp in loop 6. Cyclization by AEP is one of the proposed biosynthetic mechanisms proposed as being central to the cyclization of SFTI-1 (Mulvenna, J. P., et al., (2005) J. Biol. Chem. 280, 32245-32253) in Helianthus annuus, however the gene sequence corresponding to amino acids surrounding the expressed protein sequence does not indicate the involvement of Gly-Leu-Pro tripeptide motifs regarded as essential in cyclotide precursor proteins (Gillon, A. D., et al., (2008) Plant J. 53, 505-515; Saska, I., et al., (2007) J. Biol. Chem. 282, 29721-29728). In addition, sequence alignments of cyclic trypsin inhibitors MCoTI-1 and MCoTI-II from Momordica cochinchinensis with related linear trypsin inhibitors (Hernandez, J.-F., et al., (2000) Biochemistry 39, 5722-5730 suggest that they exhibit C-terminal Gly as unprocessed precursor proteins. Therefore, it is tempting to speculate that cyclization strategies utilized by organisms in the production of cyclotides and other cyclic proteins vary between species, based in part upon the capabilities of available processing enzymes.

The amino acid sequence of cyclotide Cter M (FIG. 9), while bearing the classic hallmark of other cyclotides, including the spacing of the six conserved Cys residues and a CCK fold, as determined by NMR, has some sequence differences that suggest a greater flexibility in cyclotide processing than has hitherto been reported. Its conserved Asn residue at the C-terminus of the mature cyclotide domain suggests processing by AEP like other cyclotides but the residue immediately following this Asn in the Cter M precursor, His, has not been seen in any other cyclotide genes, which exclusively contain a small amino acid (usually Gly or Ala at this position).

Fabaceae Cyclotide Gene Organization

All cyclotides reported to date from other plant families are biosynthesized from precursor proteins that are encoded by dedicated genes. In contrast, the cyclotides of C. ternatea are expressed from genes having a markedly different configuration.

The gene encoding the Cter M cyclotide is shown in FIG. 10. In contrast to the configuration seen other plant families, the gene in C. ternatea encodes a precursor that comprises the cyclotide amino acid sequence along with an albumin subunit sequence. While not limiting the present invention to any particular model, the cyclotide gene encoding Cter Mappears to have hijacked an albumin gene, encoding the cyclotide in place of subunit b of the albumin. Pea albumin 1 subunit b (PA1b) is a 37-amino acid protein isolated from pea seeds (Pisum sativum), that has been shown to act as a potent insecticidal agent (Da Silva, P., et al., (2010) J Biol Chem 285, 32689-32694). See also Nguyen, et al. J. Biol. Chem. 286(27):24275-87 (2011), incorporated herein by reference for all purposes. PA1b is characterized as a knottin owing to the three braced disulfide bonds. In an analogous fashion to the cyclotide kalata B1 (Simonsen, S. M., et al., (2008) J Biol Chem 283, 9805-9813), the three-dimensional structure of PA1b has been demonstrated to be extremely tolerant to modifications (Da Silva, supra). Furthermore, both receptor-binding and insecticidal activities of PA1b were dependent on a cluster of hydrophobic residues located on a single face of the molecule (Da Silva, supra). These data show striking parallels with recent studies highlighting the importance of the hydrophobic patch of kalata B1 in modulating insecticidal and membrane binding interactions (Simonsen, supra, Huang, Y. H., et al., (2009) J Biol Chem 284, 20699-20707).

The current study shows that fully folded cyclotides are produced naturally in a member of the Fabaceae plant family, demonstrating both the presence and capabilities of necessary post-translational modification infrastructure involved in their biosynthesis. Although the sequences of novel cyclotides described in this study are mostly conservative permutations of previously identified proteins, the sequence variability displayed at putative cyclization sites in a number of C. ternatea cyclotides suggests that alternative biosynthetic cyclization mechanisms may be responsible. In particular, cyclotides described in this study possessing novel putative N-termini are suggestive of significantly different, or additional specialized capabilities with respect to enzymes supporting their cyclization. Numerous species within the Fabaceae are known to possess legumain, an AEP which was initially discovered as the enzyme responsible for peptide ligation in the post-translational processing of the lectin concanavalin A from Canavalia ensiformis (Jackbean) seeds (Carrington, D. M., et al., (1985) Nature 313, 64-67) If a homologous enzyme exists in C. ternatea, its presence could explain the existence of cyclotides with unusual sequence at their putative cyclization sites characterized described in the current study, as legumain activity has been reported across a wide range of Asn-Xaa bonds (Abe, Y., et al., (1993) J Biol Chem 268, 3525-3529).

These considerations, coupled with the importance of Fabaceous crops to nutrition, industry and agriculture, give Fabaceae species special relevance in future cyclotide-focused transgenic studies. Cyclotides have been previously exploited as ultra-stable scaffolds for the presentation of bioactive epitopes (Gao, Y., et al., (2010) Bioorg Med Chem 18, 1331-1336; Gunasekera, S., et al., (2008) J Med Chem 51, 7697-7704; Thongyoo, P., et al., (2009) J Med Chem 52, 6197-6200). Fabaceae plants represent novel vectors for biotechnological production of a broader range of designer cyclic proteins than previously considered possible. The demonstrated capacity of C. ternatea to produce fully formed cyclotides suggests that cyclotides with optimized resistance traits and/or possessing other traits of pharmaceutical, economic or agricultural significance may be readily expressed in a functional form within Fabaceae species. Due to the previously demonstrated efficacy of naturally occurring cyclotides as insecticidal (Barbeta, B. L., et al. (2008) Proc. Nat'l. Acad. Sci. USA 105, 1221-1225, Jennings, C., et al., (2001) Proc. Nat'l. Acad. Sci. USA 98, 10614-10619) and nematocidal (Colgrave, M. L., et al., (2008) Biochemistry 47, 5581-5589, Colgrave, M. L., et al., (2008) Chembiochem 9, 1939-1945, Colgrave, M. L., et al., (2009) Acta Trop 109, 163-166, and Colgrave, M. L., et al., (2010) Antimicrob Agents Chemother 54, 2160-6) agents, it is believed that the natural role of cyclotides is as plant defence agents, making them excellent candidates for incorporation in transgenic crops to provide resistance against important pests.

Cyclotides are known to possess potent in vitro anthelmintic activity against human, canine and ovine nematode parasites. Root-knot nematodes, which are estimated to cause more than $100 billion of crop losses worldwide (Koenning, S. R., et al., (1999) J Nematol 31, 587-618, Opperman, C. H., et al., (2008) Proc Natl Acad Sci USA 105, 14802-14807) represent obvious targets in this regard, however the efficacy of cyclotides against them remains untested. Cyclotides are differentially expressed among plant tissues, presumably in order to counter the selective pressures specific to their respective microenvironments (Trabi, M. & Craik, D. J. (2004) Plant Cell 16, 2204-2216). Cyclotide Vhr-1 from Viola hederacea is expressed exclusively in the root tissue of Viola hederaceae.

The present invention contemplates linear molecules of from about 20 amino acids to about 100 amino acids and more preferably from about 25 amino acids to about 50 amino acids such as about 30 amino acids which are used as substrates for cyclization reactions. The resulting cyclized molecules having the same or functionally similar structure as the cyclic framework as herein described.

As stated above, the present invention extends to a range of derivatives, homologues and analogues of the molecular framework. A derivative includes parts, fragments, portions and linear forms. One particularly useful linear form is referred to herein as “uncycles” which are acyclic permutations of the cyclic molecular framework. Circular permutation involves the synthesis or expression of proteins having amino- and carboxy-termini permuted from their native locality. In relation to the naturally occurring cyclic molecular frameworks of the present invention, such molecules do not have native amino and carboxy termini. However, cyclic permutation permits a range of different linear molecules to be prepared with different amino and carboxy termini. An uncycle may have increased activity relative to its cyclic form or no activity or may exhibit antagonist activity. An uncycle exhibiting no activity may nevertheless be useful, for example, in the generation of antibodies.

By way of example only, particularly preferred CCK molecules comprise six cysteine residues and, hence, have six loops in the backbone which can be opened to form six possible topologically distinct acyclic permutants. Similarly, each of the 6 linear topologies may also be cyclized. This aspect of the present invention provides, therefore, for the cyclization of any linear topology into a CCK framework.

The uncycles of the present invention may be useful as antagonists of the cyclic molecular framework or may themselves exhibit useful activity.

Still another aspect of the present invention is directed to antibodies to the molecular framework of the present invention. Such antibodies may be monoclonal or polyclonal. Polyclonal antibodies are particularly preferred. Antibodies may be made using standard techniques.

The cyclic molecular frameworks according to the present invention are useful as therapeutic agents in animals and as anti-pathogenic agents in plants. Accordingly, the present invention provides a method for the treatment or prophylaxis of conditions or diseases in mammals, preferably humans, including the step of administering a molecular framework as hereinbefore described either without modification or having heterologous amino acids grafted thereon.

In particular, molecular frameworks may be selected or engineered for use in the treatment of neurological disorders such as acute and chronic pain, stroke, traumatic brain injury, migraine, epilepsy, Parkinson's disease, Alzheimer's disease, multiple sclerosis, schizophrenia and depression as well as cystic fibrosis and/or other respiratory diseases. The molecular framework may also be selected to treat plants against pathogen infestation and mammals including humans from viral or microbial infection.

The present invention also provides a composition comprising cyclic molecular framework molecules as hereinbefore described and a pharmaceutically acceptable carrier and/or diluent. Preferably the composition is in the form of a pharmaceutical composition.

There is also provided the use of a cyclic molecular framework in the manufacture of a medicament for the treatment or a prophylaxis of diseases or other conditions in mammals, preferably in humans.

In some embodiments, a transgenic plant is produced comprising cells transformed with at least one gene encoding the CterM or CterM-like gene described above, such that a cyclotide is expressed in at least one of its tissues of organs. The present invention encompasses transgenic plants produced in this way to express CterM or CterM-like peptides (without or without heterologous grafted peptides) in any of Fabaceae and/or non-Fabaceae plants of agricultural and biotechnological significance. These plants can be obtained by conventional techniques of plant transgenesis as are presently well known and which have been rigourously tested in these many plant species (see, e.g., Dunwell, J. M. (2000). J. Exp. Biol. 51, 487-496; and Eapen, S. (2008) Biotechnol. Adv. 26, 162-168).

Genetic elements typically or optionally included for expression of heterologous proteins in plants are known in the art. For example, binary vectors, for plant transformation are generally configured to allow propagation in multiple host cell types, may typically contain an origin of replication, a selectable marker gene cassette with appropriate promoter, multiple cloning sites in which the gene of interest and/or reporter gene can be inserted, and T-DNA borders (e.g., as reviewed by Komari, T., et al., (2006) Binary Vectors and super-binary vectors. pp. 15-42. In: Agrobacterium Protocols. Ed, Kan Wang. Methods in Molecular Biology Volume 343). The vector backbone may also include a bacterial selectable marker gene unit, plasmid mobilization functions and plasmid replication functions, as well other factors relevant to plasmid mobilization and replication in, e.g., Agrobacterium. Examples include pCAMBIA series (see, e.g., the cambia.org site on the world wide web) and pPZP series (Hajdukiewicz, et al., (1994) The small, versatile pPZP family of Agrobacterium binary vectors for plant transformation. Plant Mol. Biol. 25, 989-994.). In some embodiments, binary vectors are used in conjunction with helper plasmids that provide one or more functions, e.g., for replication.

Methods of transformation of plant cells are known in the art. Commonly used methods typically comprise Agrobaterium-mediated transformation. See e.g., Eapen S, et al., (1987) Cultivar dependence of transformation rates in mothbean after co-cultivation of protoplasts with Agrobacterium tumefaciens. Theor Appl Genet. 75: 207-10; Krishnamurthy K V, et al., (2000) Agrobacterium mediated transformation of chickpea (Cicer arietinum L.) embryo axes. Plant Cell Rep 19: 235-40; and Sharma K K, et al., (2006) Agrobacterium-mediated production of transgenic pigeonpea (Cajanus cajan L Millsp) expressing synthetic Bt cryIAb gene. In vitro Cell Dev Biol Plant 42: 165-73. In Agrobacterium-mediated transformation, embryonic axes and cotyledonary nodes are most commonly used as explants, although shoot apices, leaf, callus, seed, stem segments or other plant tissues are also used. Other transformation techniques that find use with the present invention include but are not limited to particle gun bombardment (e.g., Kamble S, et al., (2003) A protocol for efficient biolistic transformation of mothbean (Vigna aconitifolia L. Marechal). Plant Mol Biol Report 21: 457a-j; Indurker S, et al., (2007) Plant Cell Rep 26: 755-63), electroporation of intact axillary buds (Chowrira G M, et al., (1996) Mol Biotechnol 5:85-96) and electroporation-PEG mediated transformation using protoplasts (Kohler F, et al., (1987a) Plant Cell Rep 6: 313-7 and Kohler F, et al., (1987b) Plant Sci Lett 53: 87-91.). Techniques used may vary according to the transgenic plant species to be generated. Plant regeneration is generally by de novo organogenesis, although somatic embryogenesis or proliferation of shoot meristems from areas surrounding a shoot bud are also options.

Transformation of plants may be assessed by a number of different methods. For example, plant tissues may be assessed for the presence of the gene of interest, or an RNA or protein produced therefrom, by standard hybridization, antibody, or other functional tests that are standard in the art. Further, selectable markers may be used to confirm transformation. For example selectable markers may include neomycin phosphotransferase (nptII) gene (Valvekens et al., (1988) Proc. Natl. Acad. Sci. USA 85: 5536-5540) and/or Phosphomannose isomerase (Boscariol et al., (2003) Plant Cell Rep 22, 122-128), which confer resistance to antibiotics (kanamycin, paromomycin), and eliminate natural plant toxicity to mannose, respectively. The selection of a particular selectable selectable marker for use is typically based upon plant species to be transformed and downstream applications for which the transformed cells or tissues will be used (e.g., toxicity studies).

Numerous diverse plant species have been genetically transformed with foreign DNA, using several different gene insertive techniques. In some embodiments edible plants may be selected for expression of cyclotides such that the cyclotide (e.g., a cyclotide having nutrient or therapeutic function or activity) may be delivered to a subject in an edible material. In such embodiments, the host plant selected for genetic transformation preferably has edible tissue in which the cyclotide is expressed, such as the fruit, leaves, stems, sees, or roots, such that the tissue may be consumed by a human or an animal for whom the cyclotide is intended. For example, the Fabaceae family of plants comprises soy plants (e.g., Glycine max), which contains edible seeds and tissues, and from which numerous edible materials may be produced. A cyclotide may also be produced in a non-edible plant and may be isolated and used or administered in standard fashion such as may be used for any agricultural, pharmaceutical or nutrient substance or chemical.

As will be readily appreciated by those skilled in the art, the route of administration and the nature of the pharmaceutically acceptable carrier will depend on the nature of the condition and the mammal to be treated. It is believed that the choice of a particular carrier or delivery system, and route of administration could be readily determined by a person skilled in the art. In the preparation of any formulation containing the peptide actives care should be taken to ensure that the activity of the framework is not destroyed in the process and that the framework is able to reach its site of action without being destroyed. In some circumstances it may be necessary to protect the framework by means known in the art, such as, for example, micro encapsulation. Similarly the route of administration chosen should be such that the peptide reaches its site of action. In view of the improved stability and/or bioavailability of the cyclic frameworks relative to their “linear” counterparts, a wider range of formulation types and routes of administration is available.

The pharmaceutical forms suitable for injectable use include sterile injectable solutions or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions. They should be stable under the conditions of manufacture and storage and may be preserved against the contaminating action of microorganisms such as bacteria or fungi. The solvent or dispersion medium for the injectable solution or dispersion may contain any of the conventional solvent or carrier systems for peptide actives, and may contain, for example, water, ethanol, polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about where necessary by the inclusion of various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal and the like. In many cases, it will be preferable to include agents to adjust osmolality, for example, sugars or sodium chloride. Preferably, the formulation for injection will be isotonic with blood. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin. Pharmaceutical forms suitable for injectable use may be delivered by any appropriate route including intravenous, intramuscular, intracerebral, intrathecal injection or infusion.

Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze-drying technique which yield a powder of the active ingredient plus any additional desired ingredient from previously sterile-filtered solution thereof.

When the active ingredient is suitably protected, it may be orally administered, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsule, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet. For oral therapeutic administration, the active compound may be incorporated; with excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like. Such compositions and preparations preferably contain at least 1% by weight of active compound. The percentage of the compositions and preparations may, of course, be varied and may conveniently be between about 5 to about 80% of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that a suitable dosage will be obtained.

The tablets, troches, pills, capsules and the like may also contain the components as listed hereafter. A binder such as gum, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such a sucrose, lactose or saccharin may be added or a flavouring agent such as peppermint, oil of wintergreen, or cherry flavouring. When the dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier. Various other materials may be present as coatings or to otherwise modify the physical form of the dosage unit. For instance, tablets, pills, or capsules may be coated with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavouring such as cherry or orange flavour. Of course, any material used in preparing any dosage unit form should be pharmaceutically pure and substantially non-toxic in the amounts employed. In addition, the active compound(s) may be incorporated into sustained-release preparations and formulations.

The present invention also extends to any other forms suitable for administration, for example, topical application such as creams, lotions and gels, or compositions suitable for inhalation or intranasal delivery, for example solutions or dry powders.

Parenteral dosage forms are preferred, including those suitable for intravenous, intrathecal, or intracerebral delivery.

Pharmaceutically acceptable carriers and/or diluents include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, use thereof in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.

It is especially advantageous to formulate parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the mammalian subjects to be treated; each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the novel dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the active material and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active material for the treatment of disease in living subjects having a diseased condition in which bodily health is impaired as herein disclosed in detail.

The principal active ingredient is compounded for convenient and effective administration in effective amounts with a suitable pharmaceutically acceptable carrier in dosage unit form. A unit dosage form can, for example, contain the principal active compound in amounts ranging from 0.25 μg to about 2000 mg. Expressed in proportions, the active compound is generally present in from about 0.25 μg to about 2000 mg/mL of carrier. In the case of compositions containing supplementary active ingredients, the dosages are determined by reference to the usual dose and manner of administration of the said ingredients.

The cyclic molecular frameworks of the present invention may also have useful application as anti-pathogen agents in plants. Examples of pathogens include insects, spiders, viruses, fungi and other microorganisms causing deleterious effects. In particular, molecular frameworks may be engineered for use in conferring protection from pathogen (including insect) infestation of plants; for example, protection from insect attack in cotton. Such an activity may be engineered by the introduction of appropriate amino acid residues into the molecular framework, as described above, and their use in topical applications such as, e.g. in sprays.

Accordingly, the present invention provides a method for conferring pathogen protection to a plant, including the step of administering an engineered framework as hereinbefore described. Reference to administering includes reference to the topical application in liquid, aerosol, droplet, powdered or particulate form.

EXPERIMENTAL EXAMPLES

The following examples serve to illustrate certain preferred embodiments and aspects of the present invention and are not to be construed as limiting the scope thereof.

The abbreviations used are: kB1, kalata B1; RP-HPLC, reversed-phase high performance liquid chromatography; MALDI-TOF, matrix-assisted laser desorption ionization time-of-flight; CCK, cyclic cystine knot; SFTI-1, sunflower trypsin inhibitor-1; AEP, asparaginyl endopeptidase; SPE, solid phase extraction; CHCA, α-Cyano-4-hydroxycinnamic acid; CE, collision energy.

Example 1

Isolation and Characterization from C. ternatea Seeds

Seed Extraction.

Seed material (˜0.20 g) from C. ternatea (Milgarra variety as supplied by Heritage Seeds, Rocklea, Australia) was ground in a mortar and pestle prior to solvent extraction with 100 mL of 50% (v/v) acetonitrile, 2% (v/v) formic acid. Crude extract was centrifuged for 4 min at 4,000×g, and the supernatant passed through a 0.45 micron syringe filter prior to lyophilization, yielding 430 mg material.

Solid Phase Extraction (SPE).

Crude plant extracts were redissolved in 1% (v/v) formic acid and underwent an SPE clean up step prior to further analysis. Waters C18 SPE cartridges of 100 mg to 10 g resin capacity were activated with 10 bed volumes of methanol and subsequently equilibrated with 10 bed volumes of 1% (v/v) formic acid. Following application of crude plant extracts, the cartridges were washed with a further 10 bed volumes of 1% (v/v) formic acid. Interfering substances were eluted from the cartridges in 10% (v/v) acetonitrile, and cyclotides collected in 20% to 80% (v/v) acetonitrile elution steps as separate fractions and lyophilized.

HPLC Purification.

Separation of cyclotides from crude C. ternatea extracts or SPE fractions was carried out using preparative or semi-preparative HPLC. For preparative HPLC, samples were reconstituted in 10% (v/v) acetonitrile, 1% (v/v) trifluoroacetic acid and introduced to a Phenomenex C18 RP-HPLC column (Torrance, Calif., USA) (250×21.2 mm, 15 μm, 300 Å). Using a Waters 600E HPLC unit (Milford, Mass., USA), a linear 1% min⁻¹ acetonitrile gradient was delivered to the column at a flow rate of 8 mL min⁻¹ and the eluent was monitored using a dual wavelength UV detector set to 214 and 280 nm, and fractions were collected. In semi-preparative HPLC separations, a Phenomenex C18 RP-HPLC column (250×10 mm, 10 μm, 300 Å) was utilized with a flow rate of 3 mL min⁻¹. Selected cyclotides were purified to >95% purity through repetitive RP-HPLC and duplicate samples submitted for amino acid analysis.

MALDI-TOF MS.

MALDI-TOF analyses were conducted using an Applied Biosystems 4700 TOF-TOF Proteomics Analyser (Foster City, Calif., USA). Samples were prepared through 1:1 dilution with matrix consisting of 5 mg mL⁻¹ CHCA in 50% (v/v) acetonitrile, 1% (v/v) formic acid prior to spotting on a stainless steel MALDI target. MALDI-TOF spectra were acquired in reflector positive operating mode with source voltage set at 20 kV and Gridl voltage at 12 kV, mass range 1000-5000 Da, focus mass 1500 Da, collecting 1500 shots using a random laser pattern and with a laser intensity of 3500. External calibration was performed by spotting CHCA matrix 1:1 with Applied Biosystems Sequazyme Peptide Mass Standards Kit calibration mixture diluted 1:400 as described previously (Saska, I., et al., (2008) J. Chromatogr. B 872, 107-114).

Enzymatic Digestion.

Prior to tandem MS analyses, cyclotides were cleaved to produce linearized fragments following reduction and alkylation to prevent re-oxidation. Lyophilized samples were reconstituted in 100 mM NH₄HCO₃ (pH 8) and a 10 μL portion was reduced by addition of 10 μL of 10 mM dithiothreitol and incubation at 60° C. for 30 min in a nitrogenous atmosphere. Incubation with a further 10 μL of 100 mM iodoacetamide followed for 30 min at RT. Samples were split into three ˜7 μL fractions for digestion by endoproteinase Glu-C (Sigma P2922), TPCK-treated bovine trypsin (Sigma T1426) or a combination of both enzymes. In the case of the single-enzyme digests, a sample of ˜7 μL received 5 μL of 40 ng μL⁻¹ enzyme and 5 μL of 100 mM NH₄HCO₃. For the double-enzyme digest, a sample of ˜7 μL was mixed with 5 μL of 40 ng μL⁻¹ of each enzyme. All three digests were incubated at 37° C. for 3 h and then quenched with formic acid. All samples were retained at 4° C. until further analysis.

Nanospray on QSTAR Pulsar.

Reduced and enzymatically digested samples were processed using C18 ziptips (Millipore) to remove salts and elicit a solvent exchange from aqueous solution to 80% (v/v) acetonitrile, 1% (v/v) formic acid. Samples (3 μL) were introduced to nanospray tips (Proxeon ES380) and 900 V was applied to the tip to induce nanoelectrospray ionization on a QSTAR Pulsar I QqTOF mass spectrometer (Applied Biosystems). The collision energy (CE) was varied from 10 to 60 V. Both TOF and product ion mass spectra were acquired and manually assigned using Analyst QS 1.1 Software.

Cter cyclotide peptides from seeds are aligned in Table 1, below.

TABLE 1 SEQ Exp. Theor. ID Exp. mass mass Error NO: Peptide Amino acid sequence^(a) m/z (Da) (Da) Δ(ppm) Subfamily 13 Cter A GVIPCGESCVFIPC-ISTVIGCSCKNKVCYRN 1090.07 3267.19 3267.49 −91.8 Bracelet 8 Cter B G-VPCAESCVWIPCTVTALLGCSCKDKVCYLN 1084.58 3250.75 3250.45 92.6 Bracelet 9 Cter C G-VPCAESCVWIPCTVTALLGCSCKDKVCYLD 1084.93 3251.76 3251.43 99.2 Bracelet 11 Cter D G-IPCAESCVWIPCTVTALLGCSCKDKVCYLN 1089.26 3264.76 3264.46 91.0 Bracelet 10 Cter E G-IPCAESCVWIPCTVTALLGCSCKDKVCYLD 1089.61 3265.79 3265.45 105.2 Bracelet 19 Cter F G-IPCGESCVFIPC-ISSVVGCSCKSKVCYLD 1536.48 3070.94 3071.34 −132.7 Bracelet 15 Cter G G-LPCGESCVFIPC-ITTVVGCSCKNKVCYNN 1043.15 3126.42 3126.36 19.0 Bracelet 16 Cter H G-LPCGESCVFIPC-ITTVVGCSCKNKVCYND 1043.48 3127.43 3127.34 26.8 Bracelet 22 Cter I GTVPCGESCVFIPC-ITGIAGCSCKNKVCYIN 1052.33 3153.96 3154.39 −135.7 Bracelet 23 Cter J GTVPCGESCVFIPC-ITGIAGCSCKNKVCYID 1052.67 3154.99 3155.58 −122.2 Bracelet 17 Cter K H-EPCGESCVFIPC-ITTVVGCSCKNKVCY-N 1037.14 3108.39 3108.31 24.4 Bracelet 18 Cter L H-EPCGESCVFIPC-ITTVVGCSCKNKVCY-D 1037.47 3109.39 3109.30 31.3 Bracelet ^(a)Ile and Leu were determined by amino acid analysis where sufficient material was available, or assigned based upon homology with published cyclotide sequences.

Example 2

Isolation, Characterization and Synthesis of Cyclotides from C. ternatea Leaves Leaf Extraction.

Leaf material (˜3.5 g) from C. ternatea plants (grown in St Lucia, Brisbane, Australia) was ground in a mortar and pestle prior to solvent extraction with 20 mL of 50% (v/v) acetonitrile, 2% (v/v) formic acid. Crude extract was centrifuged for 4 min at 4,000×g, and the supernatant passed through a 0.45 micron syringe filter prior to lyophilization.

Mass Spectrometry.

As described for the seed extracts, above, the aqueous leaf extract of was treated by reduction to break disulfide bonds, alkylation to block reactive cysteine residues, and digestion with endoproteinase Glu-C to linearize any cyclic peptides present in the extract. MALDI-TOF analyses were conducted using an Applied Biosystems 4700 TOF-TOF Proteomics Analyser (Foster City, Calif., USA) and UltrafleXtreme TOF-TOF instrument (Bruker, Bremen, Germany) as previously described (Poth, A. G., et al., (2011) ACS Chem Biol.). Linearized cyclotide-containing crude leaf extract was analyzed on a QStar® Elite hybrid LC-MS/MS system (Applied Biosystems/MDS SCIEX, Foster City, USA) equipped with a nano-electrospray ionization source. The collection of MS/MS spectra were searched against a custom-built database of cyclotides using the ERA methodology (Colgrave, et al., (2010), Biopolymers 94:592-601) using ProteinPilot. All MS/MS data were manually verified.

LC-MS/MS analyses showed a dominant peak at 20.9 min of m/z 1147.53 corresponding to a mass of 3439.60 Da for a linearized alkylated peptide (mass of native peptide 3073.60 Da). Examination of the full product ion MS/MS spectrum (FIG. 2) revealed the sequence of the peptide to be TCTLGTCYVPDCSCSWPICMKNGLPTCGE (SEQ ID NO:143) where the methionine was oxidised. The sequence was database (BLAST) searched and deduced to be a novel cyclotide. We previously reported the identification of 12 cyclotides in seed extracts from C. ternatea (Poth, et al., 2011, supra), all of which belong to the Bracelet cyclotide sub-family. This is the first report of a cyclotide belonging to the Möbius sub-family from Fabaceous plants. Using similar methods an additional six peptide sequences (including Cter A previously identified in C. ternatea seeds) were deduced and their sequences are summarized along with the original 12 sequences in FIG. 9.

NMR Spectroscopy.

Spectra were recorded at 600 and 900 MHz (Bruker Avance NMR spectrometers) on a sample containing 1 mM Cter M in 10% D₂O/90% H₂O. The two-dimensional spectra including, TOCSY, COSY and NOESY, were recorded as previously described Rosengren, K. J., et al., (2003) J. Biol. Chem. 278, 8606-8616. Distance restraints were obtained from a NOESY spectrum recorded with a 200 ms mixing time at 290 K. A family of structures that are consistent with the experimental restraints was calculated using the programs CYANA (Guntert, P. (2004) Methods Mol Biol 278, 353-378) and CNS (Brunger, A. T. (2007) Nat Protoc 2, 2728-2733). A set of 50 structures was calculated and the 20 lowest energy structures selected for further analysis. Structures were analyzed using the programs PROCHECK_NMR (Laskowski, R. A., et al., (1996) J. Biomol. NMR 8, 477-486) and PROMOTIF (Hutchinson, E. G. & Thornton, J. M. (1996) Protein Sci. 5, 212-220. MolMol (Koradi, R., et al., (1996) J. Mol. Graph. 14, 29-32) and PyMol were used to display the structural ensembles and surfaces of the peptides, respectively.

Example 3 Gene Discovery and Verification

One of the difficulties encountered when de novo analysing peptide MS/MS spectra is the inability to distinguish the isobaric residues Ile and Leu. Amino acid analysis can yield the amino acid composition, but when both residues are present in a given sequence it is not possible to determine their location. With this constraint in mind and with the aim of exploring biosynthesis of cyclotides within the Fabaceae we proceeded with gene sequence determination.

Total RNA was extracted from 97 mg leaf tissue of C. ternatea using TRIzol® LS reagent (Invitrogen). RNA was DNAse-treated (Ambion), and complementary DNA was generated using random hexamers and Superscript III reverse transcriptase (Invitrogen). A degenerate primer (Ct-For1A, 5′-CCiACNTGYGGNGARACNTG-3′ SEQ ID NO:144) and an oligo-dT primer (5′-GCCCGGG T₂₀-3′ SEQ ID NO:145) were initially used to amplify products from cDNA. Resulting PCR products were cloned into pGEM-T Easy Vector System (Promega) and independently amplified clones were sequenced. Rapid amplification of cDNA ends (RACE) was performed using the FirstChoice® RLM-RACE kit (Applied Biosystems) according to manufacturer's instructions. First strand cDNA synthesis was performed on leaf-derived RNA. Sequence-specific primers (Cter M-RACE-Rev1,5′-GGAAACACCAACCAAAATGGATGT-3′ SEQ ID NO:146; Cter M-RACE-Rev2,5′-TCACTGTTTTTGCATTAGCTGCAA-3′ SEQ ID NO:147) were used for first and second round PCR amplifications respectively. PCR products were cloned and sequenced. Primers (Cter M-SpecFor, 5′-TCCTTATTTTCATCAACTATGGCTTA-3′ SEQ ID NO:148; Cter M-SpecRev, 5′-TCATACATGATCACTTTTAGTTGG-3′ SEQ ID NO:149) were designed near the ends of the overlapping gene sequences, and used to amplify full-length transcript from leaf-derived cDNA. Total Total RNA was isolated from leaf, and used to generate cDNA. A degenerate primer was designed based upon the highly conserved PTCGETC motif (SEQ ID NO:13), and used in combination with oligo-dT to isolate partial transcripts from cDNA. Analysis of PCR products revealed a single 402 bp band. Following cloning, sequence analysis of independently amplified clones revealed that partial cyclotide sequence was embedded within a precursor protein with a strikingly different (atypical) gene architecture compared to all previously determined cyclotide gene sequences.

In all cyclotide genes elucidated to date, mature cyclotide domains are followed by a small C-terminal region (CTR) tail of 3-11 amino acids comprising a small amino acids (Gly or Ala), a strictly conserved Leu in the second position which has been postulated to play a critical role in docking to a specific binding pocket of asparaginyl endoprotease during peptide excision and ligation reactions (Koradi, R., et al., (1996) J. Mol. Graph. 14, 29-32). In the case of the C. ternatea-derived sequence, the sequence of the mature peptide is flanked on the C-terminus by a 74 amino acid tail, in which the Gly and the ‘critical’ Leu notably absent. BLAST searching of this C-terminal tail region revealed that it possessed high sequence homology to the C-terminal portion of albumin-1 proteins from a variety of Fabaceae species.

Following 5′ RACE amplification and alignment to previous sequences, a 514 bp consensus sequence was obtained. To confirm that this sequence represented a single mRNA expressed in C. ternatea leaf, primers were designed within the 5′ and 3′ untranslated regions, and a single 418 bp PCR product was amplified. Sequence analysis revealed this product was as predicted, and encoding a predicted protein of 127 amino acids (FIG. 10). The full protein sequence of the novel Fabaceae cyclotide precursor was aligned to the homologous albumin proteins identified in the initial BLAST search FIG. 18).

In the precursor protein encoding the prototypic cyclotide, kalata B1, the mature peptide sequence is flanked by 69 amino acids at the N-terminus and seven amino acids at the C-terminus, with each of the six cysteines in the precursor located within the mature kB1 sequence. In contrast, the Cter M precursor has a typical endoplasmic reticulum (ER) signal sequence of 24 amino acids, but the predicted signal peptide cleavage site immediately precedes the N-terminus of the mature cyclotide (FIGS. 11 and 19). In addition to the six cysteines present within the cyclotide domain, four cysteines are present within the albumin-like a-chain. Examples of nucleic acid encoding ER signal peptide and the corresponding peptides of Fabaceae include but are not limited to the following:

Fabaceae albumin-1 ER signal sequences: Clitoria ternatea (JF501210): Nucleotide sequence ATGGCTTACGTTAGACTTACTTCTCTTGCCGTTCTCTTCTTCCTTGCTGCTTCCGTTAT GAAGACAGAAGGA (SEQ ID NO: 127) Amino acid sequence MAYVRLTSLAVLFFLAASVMKTEG (SEQ ID NO: 128) Phaseolus vulgaris (HM240265.1): Nucleotide sequence ATGGGTTATGTTAGGGTTGCTCCTTTGGCTCTCTTCTTGCTTGCCACTTCCATGATGTTTTC GATGAAGAAGATAGAAGCT (SEQ ID NO: 150) Amino acid sequence MGYVRVAPLALFLLATSMMFSMKKIEA (SEQ ID NO: 151) Phaseolus vulgaris (GW898230.1): Nucleotide sequence ATGGGTTATGTTAGGGTTGCTCCTTTGGCTCTCTTCTTGCTTGCCACTTCCATAATGTTTCC GATGAAGAAGACAGAGGCA (SEQ ID NO: 152) Amino acid sequence MGYVRVAPLALFLLATSIMFPMKKTEA (SEQ ID NO: 153) Pisum sativum (AJ276882.1): Nucleotide sequence ATGGCTTCCGTTAAACTCGCTTCTTTGATCGTCTTGTTTGCCACATTAGGTATGTTCCTGAC AAAAAACGTAGGGGCA (SEQ ID NO: 154) Amino acid sequence MASVKLASLIVLFATLGMFLTKNVGA (SEQ ID NO: 155) Medicago truncatula (BT053249.1): Nucleotide sequence ATGACTTATGTTAAGCTCATTACTTTGGCTCTATTCCTGGTTACCACACTCTTAATGTTTCA GACAAAGAATGTTGAAGCA (SEQ ID NO:156) Amino acid sequence MTYVKLITLALFLVTTLLMFQTKNVEA (SEQ ID NO: 157) Medicago truncatula (BG584516.1): Nucleotide sequence ATGGCTTATGTTAAGCTTGCTTCTTTTGCTGTCTTCTTGCTTGCTGCATTCGTAATGTTTCC GATGAAAAAAGTAGAAGGA (SEQ ID NO: 158) Amino acid sequence MAYVKLASFAVFLLAAFVMFPMKKVEG (SEQ ID NO:159) Glycine max (D17396.1): Nucleotide sequence ATGGCTGTCTTCTTGCTTGCCACTTCCACCATAATGTTCCCAACGAAGATAGAAGCA (SEQ ID NO: 160) Amino acid sequence MAVFLLATSTIMFPTKIEA (SEQ ID NO: 161)

Synthesis

Cter M was synthesized using solid phase peptide synthesis and folded using conditions earlier established for other cyclotides (Daly, N. L., et al., (1999) Biochemistry 38, 10606-10614) including the use of 50% isopropanol in buffer. The synthetic peptide was identical to the native peptide by MS and HPLC (FIG. 22) and was noted to have relatively low solubility in water. The addition of acetonitrile greatly improved the solubility and the spectra of Cter M were thus recorded in the presence of acetonitrile. The NMR spectra of the native and synthetic Cter M peptides were recorded and found to be identical. The three-dimensional structure of Cter M was calculated with 398 distance restraints and 11 angle restraints using a simulated annealing protocol in CNS. The resulting family of structures had good structural and energetic statistics, as shown in Table 4, below.

TABLE 4 NMR and refinement statistics for Cter M. NMR distance & dihedral constraints Distance constraints Total NOE 398 Intra-residue 84 Sequential (|i − j| = 1) 149 Medium-range (|i − j| < 4) 51 Long-range (|i − j > 5) 114 Total dihedral angle restraints 11 Structure Statistics Violations (mean and s.d.) Distance constraints (Å) 0.02 ± 0.002 Dihedral angle constraints (°) 0.6 ± 0.13 Max. dihedral angle violation (°) 3 Max. distance constraint violation (Å) 0.3 Deviations from idealized geometry Bond lengths (Å) 0.003 ± 0.0002 Bond angles (°) 0.59 ± 0.03  Impropers (°) 0.49 ± 0.03  Average pairwise r.m.s.d.** (Å) Backbone 0.3 ± 0.08 Heavy 0.67 ± 0.18  Ramachandran statistics % in most favoured region 71.4 % in additionally allowed region 27.3 % in generously allowed region 1.4 **Pairwise r.m.s.d. was calculated among 20 refined structures.

The structure of Cter M is extremely stable evidenced by its resistance to heat denaturation. Spectra were recorded before and after heating the peptide at 95° C. for 5 minutes and no changes were observed in the spectra as shown in FIG. 14 a. An ensemble and ribbon representation of the three dimensional structure is shown in FIG. 14 along with a comparison with PA1b, the pea albumin whose precursor shares high sequence homology with the Cter gene. While variation in the loop regions of the two peptides is apparent, the eight-membered ring formed between loops 1 and 4 and the inter-connecting disulfide bonds (cysteine knot) shows striking similarities as evidenced by the superimposition in FIG. 14 d.

Analysis of the structures of Cter M with PROMOTIF identified a type I β-turn between residues 9-12, a type II β-turn between residues 16-19 and a type VIal β-turn between residues 22-25. A β-hairpin is recognized between residues 20-27, as shown in FIG. 14 c. This β-hairpin is invariably present in inhibitor cystine knot proteins (Pallaghy, P. K., et al., (1994) Protein Sci. 3, 1833-1839; Craik, D. J., et al., (2001) Toxicon 39, 43-60).

Example 4 Haemolytic Activity Assays

Serially diluted peptide solutions were incubated with washed human red blood cells. Following incubation, the supernatant was transferred before the UV absorbance was measured. The amount of haemolysis was calculated as the percentage of maximum lysis (1% Triton X-100 control) after adjusting for minimum lysis (PBS control). Synthetic melittin was used for comparison. The haemolytic dose necessary to lyse 50% of the RBCs (HD₅₀) was calculated using the regression constant from the linear portion of the haemolytic titration curve (Graphpad Prism software). Results are presented in FIG. 15. The HD₅₀ was determined to be 1.4 μM for melittin, 7.8 μM for kB1 and >100 μM for Cter M, showing Cter M to be mildly haemolytic.

Example 5 Larval Migration Assays

Larval Migration Assays.

The effect of kB1 and Cter M on the motility of L3-stage larvae of Haemonchus contortus was assessed using a previously described method (Colgrave, et al., 2010, Antimicrob. Agents Ch. 54:2160-2166). The larvae were incubated in PBS containing a range of peptide concentrations for 24 h in the dark in a 96-well plate format. The motility of the worms was assessed wherein sinusoidal motion was indicative of health and loss of motility or the degree of motility was indicative of poor health. Nematodes that had been incubated with cyclotides were compared to control (no-peptide) wells.

The results are shown in FIG. 16. Incubation with the cyclotides resulted in decreased motility of the nematodes as evidenced in the images. The control nematodes exhibited sinusoidal movement indicative of health (appeared extended in image on left, A), whereas the nematodes that had been treated with high concentrations of the peptides were coiled and showed very little movement or only a slight twitching (image on right, B).

Example 6 Insecticidal Assay

H. armigera larvae were obtained from the Queensland Department of Employment, Economic Development & Innovation. A feeding trial was conducted for 48 h with larvae maintained at 25° C. throughout the experiment. Larvae were given diets consisting of wheat germ, yeast, and soy flour. The test diets contained the peptide Cter M or kalata B1 (used as a positive control (Jennings, C., et al., (2001) Proc Nat'l Acad Sci USA 98, 10614-10619) and the control diet did not have any added peptide. Larvae were weighed at 0, 24 and 48 h. Following this, the larvae were photographed. Statistical differences were analyzed using a paired t-test or ANOVA test. Results are presented in FIG. 17.

Example 7 Expression of a Cyclotide-Encoding Gene in a Fabaceae Crop Plant

One aspect of this invention is the construction of transgenic plants to express either the entire cDNA encoding a cyclotide, such as Cter M (peptide sequence GLPTCGETCTLGTCYVPDCSCSWPICMKN (SEQ ID NO:25) and the PA1a albumin domain, or part thereof. Transgenic plant species may include many belonging to Fabaceae family, including soybeans (Glycine max), bean (Phaseolus vulgaris), pea (Pisum sativum), broadbean (Vicia faba), chickpea (Cicer arietinum), pigeonpea (Cajanus cajan), lupin (Lupinus spp), lentil (Lens culinaris) and cowpea (Vigna unguiculata). All of these species have been demonstrated to be amenable to genetic transformation and transgenesis (Eapen, (2008), Biotechnol Adv, 26, 162-168).

Expression cassettes are initially generated for transformation into soybean (Glycine max) using a modified pMON expression vector (Rogers, S. G., et al., (1987) Methods Enzymol. 153, 253-277). The coding sequence of the Cter M encoding gene with or without the PAIa albumin domain is fused with eGFP and cloned into the pMON530 binary vector under the control of the cauliflower mosaic virus 35S promoter or tissue specific promoters (see below). Transformation is performed as described above, and transformants are selected using 50 mg L21 kanamycin. The GFP fluorescence of transgenic plants is observed using a Zeiss confocal laser scanning microscope.

A range of promoters are utilised for assessment of CterM-GFP expression, including but not limited to CMV35S (Ealing, P. M., et al., (1994) Transgenic Res., 3, 344-354), polyubiquitin promoter (Gmubi) from soybean (Glycine max) (Hernandez-Garcia, C. M., et al., (2009) Plant Cell Rep., 28, 837-849), and monocot tissue-specific promoter from sorghum γ-kafirin seed storage protein gene (Defreitas, F. A., et al., (1994) Mol. Gen. Genet., 245, 177-186). Expression cassettes are then introduced in the soybean plant genome using Agrobacterium-mediated transformation (Eapen, S. (2008) Biotechnol Adv, 26, 162-168) (Krishnamurthy, K. V., et al., (2000) Plant Cell Rep., 19, 235-240); (Sharma, K. K., et al., (2006) In Vitro Cell. Dev. Pl., 42, 165-173). Assessment of recombinant polypeptide in various tissues and sub-cellular compartments is via fluorescence studies and proteomic analysis of tissues for presence of cyclotides. These techniques have been used successfully for many transgenic plants including cowpea, chickpea, peanut and other members of the Fabaceae family (Collinge, D. B., et al., (2010) Ann. Rev. Phytopathol. 48, 269-291).

The nucleotide sequences of the embodiments can be used to isolate corresponding sequences from other organisms, particularly other plants. In this manner, methods such as PCR, hybridization, and the like can be used to identify such sequences based on their sequence homology to the sequences set forth herein. Sequences isolated based on their sequence homology to the nucleic acid sequence in FIG. 10, or to nucleic acids encoding the polypeptides of SEQ ID NOs 1-12 and 14-26 as set forth herein or to fragments thereof are encompassed by the embodiments.

All publications and patents mentioned in the above specification are herein incorporated by reference herein in their entireties, for all purposes. Various modifications and variations of the described methods and systems of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific preferred embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention that are obvious to those skilled in the relevant fields are intended to be within the scope of the following claims.

TABLE 2 Loop Sizes # 3D Loop 1 Loop 2 Loop 3 Loop 4 Loop 5 Loop 6 struc- Database identifier class length length length length length length tures TACA1_TACTR Horseshoe crab 6 11 0 4 11 — 0 TACA2_TACTR Horseshoe crab 6 11 0 4 11 — 1 TACB1_TACTR Horseshoe crab 6 7 0 4 11 — 1 TACB2_TACTR Horseshoe crab 6 7 0 4 11 — 1 A0ZSG4_FUGRU agouti 6 6 0 5 10 — 0 A0ZSG5_FUGRU agouti 6 5 0 5 10 — 0 A0ZSG6_FUGRU agouti 6 6 0 5 10 — 0 A0ZSG7_FUGRU agouti 6 5 0 5 10 — 0 A1YL76_9PRIM agouti 6 6 0 5 10 — 0 A2ALT3_MOUSE agouti 6 6 0 5 10 — 0 A4GVF2_CANLU agouti 6 6 0 5 10 — 0 A5JUA3_9GALL agouti 6 6 0 5 10 — 0 A5JUA4_TRATE agouti 6 6 0 5 10 — 0 A5JUA5_TRASA agouti 6 6 0 5 10 — 0 A5JUA6_SYRRE agouti 6 6 0 5 10 — 0 A5JUA7_ROLRO agouti 6 6 0 5 10 — 0 A5JUA8_PERPE agouti 6 6 0 5 10 — 0 A5JUA9_POLMA agouti 6 6 0 5 10 — 0 A5JUB0_PAVMU agouti 6 6 0 5 10 — 0 A5JUB1_9GALL agouti 6 6 0 5 10 — 0 A5JUB2_POLSM agouti 6 6 0 5 10 — 0 A5JUB3_PHACC agouti 6 6 0 5 10 — 0 A5JUB4_PAVCR agouti 6 6 0 5 10 — 0 A5JUB6_MELGA agouti 6 6 0 5 10 — 0 A5JUB7_9GALL agouti 6 6 0 5 10 — 0 A5JUB9_LOPNY agouti 6 6 0 5 10 — 0 A5JUC0_LAGLG agouti 6 6 0 5 10 — 0 A5JUC1_LOPIM agouti 6 6 0 5 10 — 0 A5JUC2_LOPSD agouti 6 6 0 5 10 — 0 A5JUC3_LOPDI agouti 6 6 0 5 10 — 0 A5JUC4_GALSO agouti 6 6 0 5 10 — 0 A5JUC5_FRAPO agouti 6 6 0 5 10 — 0 A5JUC6_9GALL agouti 6 6 0 5 10 — 0 A5JUC7_CATWA agouti 6 6 0 5 10 — 0 A5JUC8_CROMA agouti 6 6 0 5 10 — 0 A5JUC9_COTIA agouti 6 6 0 5 10 — 0 A5JUD0_COTCO agouti 6 6 0 5 10 — 0 A5JUD1_CROCS agouti 6 6 0 5 10 — 0 A5JUD4_ALECH agouti 6 6 0 5 10 — 0 A5JUD5_AFRCO agouti 6 6 0 5 10 — 0 A5JUD6_ARGAR agouti 6 6 0 5 10 — 0 A5JUD7_ALERU agouti 6 6 0 5 10 — 0 A7YMS3_PERMA agouti 6 6 0 5 10 — 0 A7YMS6_PERPL agouti 6 6 0 5 10 — 0 A7YMS8_PERPL agouti 6 6 0 5 10 — 0 A9EDH6_COTIA agouti 6 6 0 5 10 — 0 A9EDJ0_COTIA agouti 6 6 0 5 10 — 0 A9JPS5_CAPHI agouti 6 6 0 5 10 — 0 AGRP_BOVIN agouti 6 6 0 5 10 — 0 AGRP_HUMAN agouti 6 6 0 5 10 — 0 AGRP_MOUSE agouti 6 6 0 5 10 — 0 AGRP_FIG agouti 6 6 0 5 10 — 0 ASIP_BOVIN agouti 6 6 0 5 10 — 0 ASIP_CALGE agouti 6 6 0 5 10 — 0 ASIP_CALGO agouti 6 6 0 5 10 — 0 ASIP_CALIA agouti 6 6 0 5 10 — 0 ASIP_CANFA agouti 6 6 0 5 10 — 0 ASIP_CEBPY agouti 6 6 0 5 10 — 0 ASIP_CERAE agouti 6 6 0 5 10 — 0 ASIP_CERMI agouti 6 6 0 5 10 — 0 ASIP_COLPO agouti 6 6 0 5 10 — 0 ASIP_ERYPA agouti 6 6 0 5 10 — 0 ASIP_FHLCA agouti 6 6 0 5 10 — 0 ASIP_GORGO agouti 6 6 0 5 10 — 0 ASIP_HORSE agouti 6 6 0 5 10 — 0 ASIP_HUMAN agouti 6 6 0 5 10 — 0 ASIP_LEOCY agouti 6 6 0 5 10 — 0 ASIP_LEORO agouti 6 6 0 5 10 — 0 ASIP_MACAR agouti 6 6 0 5 10 — 0 ASIP_MACAS agouti 6 6 0 5 10 — 0 ASIP_MACCY agouti 6 6 0 5 10 — 0 ASIP_MACFA agouti 6 6 0 5 10 — 0 ASIP_MACFU agouti 6 6 0 5 10 — 0 ASIP_MACHE agouti 6 6 0 5 10 — 0 ASIP_MACMR agouti 6 6 0 5 10 — 0 ASIP_MACMU agouti 6 6 0 5 10 — 0 ASIP_MACNE agouti 6 6 0 5 10 — 0 ASIP_MACNG agouti 6 6 0 5 10 — 0 ASIP_MACNR agouti 6 6 0 5 10 — 0 ASIP_MACRA agouti 6 6 0 5 10 — 0 ASIP_MACSI agouti 6 6 0 5 10 — 0 ASIP_MACSL agouti 6 6 0 5 10 — 0 ASIP_MACSY agouti 6 6 0 5 10 — 0 ASIP_MOUSE agouti 6 6 0 5 10 — 0 ASIP_PANPA agouti 6 6 0 5 10 — 0 ASIP_PANTR agouti 6 6 0 5 10 — 0 ASIP_PAPAN agouti 6 6 0 5 10 — 0 ASIP_PIG agouti 6 6 0 5 10 — 0 ASIP_PONPY agouti 6 6 0 5 10 — 0 ASIP_RAT agouti 6 6 0 5 10 — 0 ASIP_SEMEN agouti 6 6 0 5 10 — 0 ASIP_TRAAU agouti 6 6 0 5 10 — 0 ASIP_TRACR agouti 6 6 0 5 10 — 0 ASIP_TRAFR agouti 6 6 0 5 10 — 0 ASIP_TRAOB agouti 6 6 0 5 10 — 0 ASIP_VULVU agouti 6 6 0 5 10 — 0 B0B577_RABIT agouti 6 6 0 5 10 — 0 B0ZDU0_COTIA agouti 6 6 0 5 10 — 0 B0ZDU2_CHICK agouti 6 6 0 5 10 — 0 B0ZDU3_CHICK agouti 6 6 0 5 10 — 0 B0ZDU4_CHICK agouti 6 6 0 5 10 — 0 Q3UU47_MOUSE agouti 6 6 0 5 10 — 0 Q4JNX9_CAPHI agouti 6 6 0 5 10 — 0 Q4SEW0_TETNG agouti 6 6 0 5 10 — 0 Q4SP72_TETNG agouti 6 5 0 5 10 — 0 Q5CC33_CARAU agouti 6 6 0 5 10 — 0 Q5CC34_CARAU agouti 6 6 0 5 10 — 0 Q5CC35_CARAU agouti 6 6 0 5 10 — 0 Q5IRA5_CANFA agouti 6 6 0 5 10 — 0 Q6SGX9_CANLU agouti 6 6 0 5 10 — 0 Q6SGY0_CANLA agouti 6 6 0 5 10 — 0 Q6J648_SHEEP agouti 6 6 0 5 10 — 0 Q70Q61_CARAU agouti 6 6 0 5 10 — 0 Q70Q62_CARAU agouti 6 6 0 5 10 — 0 Q90WY7_COTJA agouti 6 6 0 5 10 — 0 Q9GLM5_PIG agouti 6 6 0 5 10 — 0 Q9PWG2_CHICK agouti 6 6 0 5 10 — 0 Q9QXJ3_RAT agouti 6 6 0 5 9 — 0 Q9W7R0_CHICK agouti 6 6 0 5 10 — 0 IAAI_AMAHP alpha envlase 6 6 0 4 7 — 0 ADO1_AGRDO bag 6 6 0 4 6 — 0 IOB1_ISYOB bag 6 6 0 4 6 — 0 PIU1_PETTU bag 6 6 0 5 6 — 0 A11GB conoserver_framework 6 8 0 3 3 — 0 VIVII ABVIA conoserver_framework 6 5 0 3 6 — 0 VIVII ABVIB conoserver_framework 6 5 0 3 6 — 0 VIVII ABVIC conoserver_framework 6 5 0 3 6 — 0 VIVII ABVID conoserver_framework 6 5 0 3 6 — 0 VIVII ABVIE conoserver_frameworkVIVII 6 5 0 3 4 — 0 ABVIF conoserver_frameworkVIVII 6 5 0 3 6 — 0 ABVIF cootant 1 conoserver_frameworkVIVII 6 5 0 3 6 — 0 ABVIG conoserver_frameworkVIVII 6 5 0 3 6 — 0 ABVIG mutant 1 conoserver_frameworkVIVII 6 5 0 3 6 — 0 ABVIH conoserver_frameworkVIVII 6 5 0 3 6 — 0 ABVII conoserver_frameworkVIVII 6 5 0 3 6 — 0 ABVIJ conoserver_frameworkVIVII 6 5 0 3 6 — 0 ABVIK conoserver_frameworkVIVII 6 5 0 3 6 — 0 ABVIL conoserver_frameworkVIVII 6 5 0 3 6 — 0 ABVIM conoserver_frameworkVIVII 6 5 0 3 4 — 0 ABVIN conoserver_frameworkVIVII 6 5 0 3 4 — 0 ABVIO conoserver_frameworkVIVII 6 5 0 3 4 — 0 AVIA conoserver_frameworkVIVII 6 6 0 3 3 — 0 Ai6.1 conoserver_frameworkVIVII 6 6 0 3 4 — 0 Ai6.2 conoserver_frameworkVIVII 6 6 0 3 4 — 0 Ai6.3 conoserver_frameworkVIVII 6 5 0 3 3 — 0 Am2766 conoserver_frameworkVIVII 6 6 0 3 3 — 0 Ar6.1 conoserver_frameworkVIVII 6 6 0 3 3 — 0 Ar6.10 conoserver_frameworkVIVII 6 4 0 4 7 — 0 Ar6.11 conoserver_frameworkVIVII 6 4 0 4 8 — 0 Ar6.12 conoserver_frameworkVIVII 6 4 0 4 6 — 0 Ar6.13 conoserver_frameworkVIVII 6 6 0 3 8 — 0 Ar6.14 conoserver_frameworkVIVII 6 5 0 3 6 — 0 Ar6.15 conoserver_frameworkVIVII 6 5 0 3 6 — 0 Ar6.16 conoserver_frameworkVIVII 6 5 0 3 6 — 0 Ar6.17 conoserver_frameworkVIVII 6 5 0 3 6 — 0 Ar6.18 conoserver_frameworkVIVII 6 5 0 3 6 — 0 Ar6.19 conoserver_frameworkVIVII 6 6 0 3 2 — 0 Ar6.2 conoserver_frameworkVIVII 6 8 0 3 3 — 0 Ar6.20 conoserver_frameworkVIVII 3 6 0 8 3 — 0 Ar6.21 conoserver_frameworkVIVII 3 6 0 8 3 — 0 Ar6.22 conoserver_frameworkVIVII 3 6 0 8 3 — 0 Ar6.24 conoserver_frameworkVIVII 3 6 0 8 3 — 0 Ar6.25 conoserver_frameworkVIVII 3 6 0 8 3 — 0 Ar6.26 conoserver_frameworkVIVII 3 6 0 7 3 — 0 Ar6.27 conoserver_frameworkVIVII 3 6 0 7 3 — 0 Ar6.28 conoserver_frameworkVIVII 3 6 0 8 3 — 0 Ar6.3 conoserver_frameworkVIVII 6 9 0 3 3 — 0 Ar6.4 conoserver_frameworkVIVII 6 6 0 2 4 — 0 Ar6.5 conoserver_frameworkVIVII 6 6 0 2 4 — 0 Ar6.6 conoserver_frameworkVIVII 6 6 0 2 4 — 0 Ar6.7 conoserver_frameworkVIVII 6 6 0 2 4 — 0 Ar6.8 conoserver_frameworkVIVII 6 6 0 2 4 — 0 Ar6.9 conoserver_frameworkVIVII 6 4 0 4 7 — 0 AsVIIA conoserver_frameworkVIVII 6 5 0 3 10 — 0 Ar6.1 conoserver_frameworkVIVII 6 5 0 3 5 — 0 Ar6.2 conoserver_frameworkVIVII 6 5 0 3 6 — 0 Ar6.3 conoserver_frameworkVIVII 6 5 0 3 6 — 0 Ar6.4 conoserver_frameworkVIVII 6 5 0 3 6 — 0 Ar6.5 conoserver_frameworkVIVII 6 5 0 3 6 — 0 Ar6.6 conoserver_frameworkVIVII 6 5 0 3 6 — 0 Ar6.7 conoserver_frameworkVIVII 6 5 0 3 6 — 0 Ar6.8 conoserver_frameworkVIVII 6 5 0 3 6 — 0 Ar6.1 conoserver_frameworkVIVII 6 6 0 3 3 — 0 Ar6.2 conoserver_frameworkVIVII 6 6 0 3 4 — 0 Ar6.3 conoserver_frameworkVIVII 6 8 0 3 3 — 0 BVIA conoserver_frameworkVIVII 6 8 0 3 3 — 0 BcB42 conoserver_frameworkVIVII 6 5 0 3 6 — 0 BcB54 conoserver_frameworkVIVII 6 5 0 3 4 — 0 Bromosleeper peptide conoserver_frameworkVIVII 6 6 0 3 3 — 0 C6.1 conoserver_frameworkVIVII 3 6 0 7 3 — 0 C6.2 conoserver_frameworkVIVII 6 6 0 3 4 — 0 C6.3 conoserver_frameworkVIVII 6 6 0 3 4 — 0 C6.4 conoserver_frameworkVIVII 6 6 0 3 4 — 0 C6.5 conoserver_frameworkVIVII 6 6 0 3 4 — 0 C6.6 conoserver_frameworkVIVII 6 6 0 3 4 — 0 C6.7 conoserver_frameworkVIVII 6 6 0 3 4 — 0 C6.8 conoserver_frameworkVIVII 6 6 0 3 4 — 0 CVIA conoserver_frameworkVIVII 6 6 0 3 4 — 0 CVIB conoserver_frameworkVIVII 6 6 0 3 4 — 0 CVIC conoserver_frameworkVIVII 6 6 0 3 5 — 0 CVID conoserver_frameworkVIVII 6 6 0 3 6 — 0 CVIE conoserver_frameworkVIVII 6 6 0 3 3 — 0 Co6.1 conoserver_frameworkVIVII 6 6 0 3 3 — 0 CaFr179 conoserver_frameworkVIVII 3 6 0 7 3 — 0 CaHr91 conoserver_frameworkVIVII 6 6 0 4 3 — 0 Cn6.1 conoserver_frameworkVIVII 6 6 0 3 3 — 0 CnVIA conoserver_frameworkVIVII 6 6 0 3 4 — 0 CnVIIA conoserver_frameworkVIVII 6 6 0 3 6 — 0 Co6.1 conoserver_frameworkVIVII 6 5 0 3 6 — 0 Co6.2 conoserver_frameworkVIVII 6 5 0 3 6 — 0 Co6.3 conoserver_frameworkVIVII 6 5 0 3 6 — 0 Co6.4 conoserver_frameworkVIVII 6 5 0 3 6 — 0 Co6.5 conoserver_frameworkVIVII 6 5 0 3 6 — 0 Co6.6 conoserver_frameworkVIVII 6 5 0 3 6 — 0 Co6.7 conoserver_frameworkVIVII 6 5 0 3 5 — 0 Conotoxin-1 conoserver_frameworkVIVII 6 5 0 3 8 — 0 Conotoxin-10 conoserver_frameworkVIVII 6 4 0 4 9 — 0 Conotoxin-12 conoserver_frameworkVIVII 6 4 0 4 9 — 0 Conotoxin-15 conoserver_frameworkVIVII 6 5 0 2 4 — 0 Conotoxin-2 conoserver_frameworkVIVII 6 4 0 4 9 — 0 Conotoxin-2.7 conoserver_frameworkVIVII 6 9 0 3 3 — 0 Conotoxin-3 conoserver_frameworkVIVII 6 5 0 2 6 — 0 Conotoxin-5 conoserver_frameworkVIVII 6 7 0 3 3 — 0 Conotoxin-6 conoserver_frameworkVIVII 6 7 0 3 3 — 0 Conotoxin-8 conoserver_frameworkVIVII 6 4 0 4 9 — 0 Conotoxin-9 conoserver_frameworkVIVII 6 6 0 3 3 — 0 Cv conotoxin conoserver_frameworkVIVII 6 8 0 3 3 — 0 Da6.1 conoserver_frameworkVIVII 6 6 0 4 4 — 0 Da6.2 conoserver_frameworkVIVII 6 6 0 4 4 — 0 Da6.3 conoserver_frameworkVIVII 6 6 0 2 4 — 0 Da6.4 conoserver_frameworkVIVII 6 6 0 3 4 — 0 Da6.5 conoserver_frameworkVIVII 6 5 0 3 3 — 0 Da6.6 conoserver_frameworkVIVII 6 9 0 4 4 — 0 Da7 conoserver_frameworkVIVII 6 9 0 4 4 — 0 Da7a conoserver_frameworkVIVII 6 7 0 3 4 — 0 DaVIIA conoserver_frameworkVIVII 6 7 0 3 4 — 0 Di6.1 conoserver_frameworkVIVII 6 6 0 2 4 — 0 Di6.2 conoserver_frameworkVIVII 6 6 0 3 4 — 0 Di6.3 conoserver_frameworkVIVII 6 5 0 3 6 — 0 E6.1 conoserver_frameworkVIVII 6 6 0 3 4 — 0 E6.2 conoserver_frameworkVIVII 6 5 0 2 6 — 0 EVIA conoserver_frameworkVIVII 6 9 0 3 3 — 0 EVIB conoserver_frameworkVIVII 6 6 0 3 4 — 0 Eb6.1 conoserver_frameworkVIVII 6 5 0 3 6 — 0 Eb6.10 conoserver_frameworkVIVII 6 5 0 3 6 — 0 Eb6.11 conoserver_frameworkVIVII 6 5 0 3 6 — 0 Eb6.12 conoserver_frameworkVIVII 6 5 0 3 6 — 0 Eb6.13 conoserver_frameworkVIVII 6 5 0 3 6 — 0 Eb6.2 conoserver_frameworkVIVII 6 5 0 3 6 — 0 Eb6.3 conoserver_frameworkVIVII 6 5 0 3 6 — 0 Eb6.4 conoserver_frameworkVIVII 6 5 0 3 6 — 0 Eb6.5 conoserver_frameworkVIVII 6 5 0 3 6 — 0 Eb6.6 conoserver_frameworkVIVII 6 5 0 3 6 — 0 Eb6.8 conoserver_frameworkVIVII 6 5 0 3 6 — 0 Eb6.9 conoserver_frameworkVIVII 6 5 0 3 6 — 0 Ep6.1 conoserver_frameworkVIVII 6 6 0 2 4 — 0 G6.1 conoserver_frameworkVIVII 6 8 0 3 3 — 0 GVIA conoserver_frameworkVIVII 6 6 0 2 6 — 0 GVIIA conoserver_frameworkVIVII 6 6 0 2 6 — 0 GVIIB conoserver_frameworkVIVII 6 6 0 2 6 — 0 Ge6.1 conoserver_frameworkVIVII 6 8 0 3 3 — 0 Gla(1)-TxVI conoserver_frameworkVIVII 6 5 0 3 3 — 0 Gla(2)-TxVI/A conoserver_frameworkVIVII 6 5 0 3 3 — 0 Gla(2)-TxVI/B conoserver_frameworkVIVII 6 5 0 3 3 — 0 Gla(3)-TxVI conoserver_frameworkVIVII 6 5 0 3 4 — 0 Gm6.1 conoserver_frameworkVIVII 6 6 0 3 3 — 0 Gm6.2 conoserver_frameworkVIVII 6 6 0 3 3 — 0 Gm6.3 conoserver_frameworkVIVII 6 6 0 3 3 — 0 Gm6.4 conoserver_frameworkVIVII 6 5 0 3 3 — 0 Gm6.5 conoserver_frameworkVIVII 6 9 0 4 4 — 0 GmVIA conoserver_frameworkVIVII 6 8 0 4 3 — 0 Im6.1 conoserver_frameworkVIVII 4 5 0 5 8 — 0 I6.1 conoserver_frameworkVIVII 6 5 0 3 6 — 0 I6.2 conoserver_frameworkVIVII 6 5 0 3 6 — 0 King-Kong 1 conoserver_frameworkVIVII 6 6 0 3 4 — 0 King-Kong 2 conoserver_frameworkVIVII 6 6 0 3 4 — 0 LVVICs conoserver_frameworkVIVII 6 5 0 3 6 — 0 LeD51 conoserver_frameworkVIVII 6 5 0 3 3 — 0 LiC42 conoserver_frameworkVIVII 6 4 0 4 8 — 0 LiC53 conoserver_frameworkVIVII 6 5 0 3 4 — 0 LiCr173 conoserver_frameworkVIVII 3 6 0 8 3 — 0 LiCr95 conoserver_frameworkVIVII 6 6 0 3 8 — 0 Lp6.1 conoserver_frameworkVIVII 6 9 0 3 3 — 0 Lt7b conoserver_frameworkVIVII 6 5 0 3 3 — 0 LtVIA conoserver_frameworkVIVII 6 4 0 4 7 — 0 LtVIB conoserver_frameworkVIVII 6 5 0 3 6 — 0 LtVIC conoserver_frameworkVIVII 6 5 0 2 6 — 0 LtVID conoserver_frameworkVIVII 6 6 0 3 8 — 0 LtVIE conoserver_frameworkVIVII 6 6 0 3 8 — 0 LtVIIA conoserver_frameworkVIVII 6 5 0 3 4 — 0 Lv6.1 conoserver_frameworkVIVII 6 6 0 3 4 — 0 LvVIA.1 conoserver_frameworkVIVII 6 5 0 4 6 — 0 LvVIA.2 conoserver_frameworkVIVII 6 5 0 4 6 — 0 LvVIA.3 conoserver_frameworkVIVII 6 5 0 4 6 — 0 LvVIB.1 conoserver_frameworkVIVII 6 5 0 4 6 — 0 LvVIB.2 conoserver_frameworkVIVII 6 5 0 4 6 — 0 LvVICb conoserver_frameworkVIVII 6 5 0 3 6 — 0 LeVID conoserver_frameworkVIVII 6 5 0 3 6 — 0 M1 conoserver_frameworkVIVII 6 5 0 3 6 — 0 M12 conoserver_frameworkVIVII 6 5 0 3 6 — 0 M15 conoserver_frameworkVIVII 6 5 0 3 6 — 0 M19 conoserver_frameworkVIVII 6 5 0 3 4 — 0 M23 conoserver_frameworkVIVII 6 5 0 3 6 — 0 M25 conoserver_frameworkVIVII 6 5 0 3 4 — 0 M26 conoserver_frameworkVIVII 6 5 0 3 6 — 0 M6.1 conoserver_frameworkVIVII 6 6 0 3 3 — 0 M6.2 conoserver_frameworkVIVII 6 6 0 3 4 — 0 MVIA conoserver_frameworkVIVII 6 6 0 3 3 — 0 MVIB conoserver_frameworkVIVII 6 6 0 3 3 — 0 MVIC conoserver_frameworkVIVII 6 6 0 3 4 — 0 MVID conoserver_frameworkVIVII 6 6 0 3 4 — 0 MVIIA conoserver_frameworkVIVII 6 6 0 3 4 — 5 MVIIB conoserver_frameworkVIVII 6 6 0 3 4 — 0 MVIIC conoserver_frameworkVIVII 6 6 0 3 5 — 2 MVIID conoserver_frameworkVIVII 6 6 0 3 4 — 0 MaI51 conoserver_frameworkVIVII 6 5 0 3 3 — 0 MaIr137 conoserver_frameworkVIVII 6 8 0 3 3 — 0 MaIr193 conoserver_frameworkVIVII 6 8 0 3 3 — 0 MaIr332 conoserver_frameworkVIVII 6 6 0 3 4 — 0 MaIr34 conoserver_frameworkVIVII 6 9 0 3 3 — 0 MaIr94 conoserver_frameworkVIVII 6 8 0 3 10 — 0 MgI42 conoserver_frameworkVIVII 6 5 0 3 6 — 0 MgIr112 conoserver_frameworkVIVII 6 5 0 4 4 — 0 MgIr93 conoserver_frameworkVIVII 6 5 0 3 6 — 0 MgIr99 conoserver_frameworkVIVII 6 5 0 3 7 — 0 MiFr92 conoserver_frameworkVIVII 6 6 0 4 8 — 0 MiFr93 conoserver_frameworkVIVII 6 5 0 3 6 — 0 MiFr95 conoserver_frameworkVIVII 6 5 0 4 8 — 0 Mik41 conoserver_frameworkVIVII 6 5 0 3 6 — 0 Mik42 conoserver_frameworkVIVII 6 6 0 2 9 — 0 Ml6.1 conoserver_frameworkVIVII 6 5 0 3 6 — 0 Ml6.2 conoserver_frameworkVIVII 6 5 0 3 6 — 0 Ml6.3 conoserver_frameworkVIVII 6 5 0 3 6 — 0 Ml6.4 conoserver_frameworkVIVII 6 6 0 2 8 — 0 Mr6.1 conoserver_frameworkVIVII 6 6 0 3 4 — 0 Mr6.2 conoserver_frameworkVIVII 6 6 0 3 4 — 0 Mr6.3 conoserver_frameworkVIVII 6 6 0 3 4 — 0 MrVIA conoserver_frameworkVIVII 6 9 0 4 4 — 0 MrVIB conoserver_frameworkVIVII 6 9 0 4 4 — 1 NgVIA conoserver_frameworkVIVII 6 8 0 3 4 — 0 Om6.1 conoserver_frameworkVIVII 6 8 0 4 4 — 0 Om6.2 conoserver_frameworkVIVII 6 6 0 3 3 — 0 Om6.3 conoserver_frameworkVIVII 6 6 0 3 4 — 0 Om6.4 conoserver_frameworkVIVII 6 6 0 2 4 — 0 Om6.5 conoserver_frameworkVIVII 6 8 0 3 3 — 0 Om6.6 conoserver_frameworkVIVII 6 9 0 4 4 — 0 P2a conoserver_frameworkVIVII 6 6 0 3 4 — 0 P2b conoserver_frameworkVIVII 6 8 0 3 4 — 0 P2c conoserver_frameworkVIVII 6 8 0 3 4 — 0 P6.1 conoserver_frameworkVIVII 6 6 0 3 4 — 0 PVIA conoserver_frameworkVIVII 6 6 0 3 4 — 0 PVIIA conoserver_frameworkVIVII 6 6 0 3 3 — 2 Pn6.1 conoserver_frameworkVIVII 6 6 0 3 4 — 0 Pn6.10 conoserver_frameworkVIVII 3 6 0 8 3 — 0 Pn6.11 conoserver_frameworkVIVII 3 6 0 8 3 — 0 Pn6.12 conoserver_frameworkVIVII 6 5 0 3 3 — 0 Pn6.13 conoserver_frameworkVIVII 6 8 0 3 3 — 0 Pn6.14 conoserver_frameworkVIVII 6 9 0 4 4 — 0 Pn6.2 conoserver_frameworkVIVII 6 6 0 2 4 — 0 Pn6.3 conoserver_frameworkVIVII 6 6 0 3 4 — 0 Pn6.5 conoserver_frameworkVIVII 6 6 0 3 3 — 0 Pn6.6 conoserver_frameworkVIVII 6 5 0 3 3 — 0 Pn6.7 conoserver_frameworkVIVII 6 9 0 3 3 — 0 Pn6.8 conoserver_frameworkVIVII 6 5 0 3 3 — 0 Pn6.9 conoserver_frameworkVIVII 6 5 0 3 3 — 0 PnVIA conoserver_frameworkVIVII 6 9 0 3 3 — 0 PnVIB conoserver_frameworkVIVII 6 8 0 3 3 — 0 PnVIIA conoserver_frameworkVIVII 6 5 0 3 4 — 0 Pn6.1 conoserver_frameworkVIVII 6 6 0 3 3 — 0 PnIA conoserver_frameworkVIVII 6 9 0 3 3 — 0 PnIIA conoserver_frameworkVIVII 6 5 0 3 6 — 0 Qc6.1 conoserver_frameworkVIVII 6 9 0 3 3 — 0 Qc6.2 conoserver_frameworkVIVII 6 8 0 3 3 — 0 QcVIA conoserver_frameworkVIVII 2 3 0 4 4 — 0 RVIA conoserver_frameworkVIVII 6 6 0 2 6 — 0 RVIIA conoserver_frameworkVIVII 6 5 0 3 4 — 0 S6.1 conoserver_frameworkVIVII 6 6 0 3 4 — 0 S6.10 conoserver_frameworkVIVII 6 5 0 3 6 — 0 S6.11 conoserver_frameworkVIVII 6 5 0 3 4 — 0 S6.2 conoserver_frameworkVIVII 6 5 0 2 4 — 0 S6.6 conoserver_frameworkVIVII 6 8 0 3 5 — 0 S6.7 conoserver_frameworkVIVII 6 6 0 2 8 — 0 S6.8 conoserver_frameworkVIVII 6 6 0 3 3 — 0 SO3 conoserver_frameworkVIVII 6 6 0 3 4 — 1 SO4 conoserver_frameworkVIVII 6 7 0 2 6 — 0 SO5 conoserver_frameworkVIVII 6 6 0 2 6 — 0 SVIA conoserver_frameworkVIVII 6 5 0 2 4 — 0 SVIA mutant 1 conoserver_frameworkVIVII 6 5 0 2 4 — 0 SVIB conoserver_frameworkVIVII 6 8 0 3 5 — 1 SVIE conoserver_frameworkVIVII 6 6 0 3 3 — 0 SmVIA conoserver_frameworkVIVII 6 6 0 3 3 — 0 SmVIIA conoserver_frameworkVIVII 6 7 0 3 9 — 0 St6.1 conoserver_frameworkVIVII 6 6 0 3 4 — 0 St6.2 conoserver_frameworkVIVII 6 8 0 3 4 — 0 St6.3 conoserver_frameworkVIVII 6 8 0 2 6 — 0 TVIA conoserver_frameworkVIVII 6 6 0 2 6 — 0 TVIIA conoserver_frameworkVIVII 6 3 0 4 4 — 1 TeA53 conoserver_frameworkVIVII 6 5 0 3 4 — 0 Textile convaissed conoserver_frameworkVIVII 2 3 0 4 4 — 0 peptide Ts6.1 conoserver_frameworkVIVII 6 5 0 4 3 — 0 Ts6.2 conoserver_frameworkVIVII 6 5 0 3 4 — 0 Ts6.3 conoserver_frameworkVIVII 6 5 0 3 3 — 0 Ts6.4 conoserver_frameworkVIVII 3 6 0 8 3 — 0 Ts6.5 conoserver_frameworkVIVII 3 6 0 8 3 — 0 Ts6.6 conoserver_frameworkVIVII 3 6 0 8 3 — 0 Ts6.7 conoserver_frameworkVIVII 3 6 0 8 3 — 0 Tx6.1 conoserver_frameworkVIVII 6 6 0 4 4 — 0 Tx6.2 conoserver_frameworkVIVII 6 6 0 3 4 — 0 Tx6.3 conoserver_frameworkVIVII 6 5 0 3 4 — 0 Tx6.4 conoserver_frameworkVIVII 6 8 0 3 3 — 0 TxIA/TxVIA conoserver_frameworkVIVII 6 6 0 3 4 — 2 TxIB/TxVIB conoserver_frameworkVIVII 6 6 0 3 4 — 0 TXMEKL-011 conoserver_frameworkVIVII 6 5 0 3 3 — 0 TxMEKL- conoserver_frameworkVIVII 6 5 0 3 5 — 0 022/tXMEKL-021 TxMEKL- conoserver_frameworkVIVII 6 5 0 3 4 — 0 0511/TxMEKL-0522 TxMEKL-033 conoserver_frameworkVIVII 6 5 0 3 4 — 0 precarsor TxMEKL-P2 conoserver_frameworkVIVII 6 5 0 4 6 — 0 TxMKLT1-0111 conoserver_frameworkVIVII 6 6 0 3 4 — 0 TxMKLT1-0141 conoserver_frameworkVIVII 6 6 0 2 4 — 0 TxMKLT1-015 conoserver_frameworkVIVII 6 6 0 3 4 — 0 TxMKLT1-0211 conoserver_frameworkVIVII 6 5 0 3 3 — 0 TxMKLT1-032 conoserver_frameworkVIVII 6 9 0 4 4 — 0 TxO1 conoserver_frameworkVIVII 6 8 0 2 4 — 0 TxO2 conoserver_frameworkVIVII 6 5 0 3 3 — 0 TxO3 conoserver_frameworkVIVII 6 5 0 3 3 — 0 TxO4 conoserver_frameworkVIVII 6 8 0 3 3 — 0 TxO5 conoserver_frameworkVIVII 6 6 0 3 4 — 0 TxO6 conoserver_frameworkVIVII 6 9 0 4 4 — 0 TxVII conoserver_frameworkVIVII 6 6 0 3 3 — 1 TxVIIA conoserver_frameworkVIVII 6 5 0 3 4 — 0 Vc6.3 conoserver_frameworkVIVII 6 8 0 2 4 — 0 Vc6.4 conoserver_frameworkVIVII 6 8 0 3 3 — 0 Vc6.6 conoserver_frameworkVIVII 6 5 0 3 3 — 0 VcVIA conoserver_frameworkVIVII 6 6 0 2 4 — 0 VcVIB conoserver_frameworkVIVII 6 6 0 4 3 — 0 VcVIC conoserver_frameworkVIVII 6 6 0 3 4 — 0 VeG52 conoserver_frameworkVIVII 6 5 0 3 4 — 0 ViKr33 conoserver_frameworkVIVII 6 5 0 4 8 — 0 ViKr92 conoserver_frameworkVIVII 6 8 0 3 3 — 0 Vn6.1 conoserver_frameworkVIVII 6 5 0 3 4 — 0 Vn6.10 conoserver_frameworkVIVII 6 8 0 3 3 — 0 Vn6.11 conoserver_frameworkVIVII 6 8 0 3 3 — 0 Vn6.12 conoserver_frameworkVIVII 6 10 0 3 3 — 0 Vn6.13 conoserver_frameworkVIVII 6 6 0 3 3 — 0 Vn6.14 conoserver_frameworkVIVII 6 5 0 3 4 — 0 Vn6.15 conoserver_frameworkVIVII 6 5 0 3 4 — 0 Vn6.16 conoserver_frameworkVIVII 6 4 0 4 8 — 0 Vn6.17 conoserver_frameworkVIVII 6 4 0 4 8 — 0 Vn6.18 conoserver_frameworkVIVII 4 4 0 4 8 — 0 Vn6.19 conoserver_frameworkVIVII 3 7 0 8 3 — 0 Vn6.2 conoserver_frameworkVIVII 6 5 0 3 4 — 0 Vn6.20 conoserver_frameworkVIVII 3 6 0 8 3 — 0 Vn6.21 conoserver_frameworkVIVII 3 6 0 8 3 — 0 Vn6.22 conoserver_frameworkVIVII 3 8 0 8 3 — 0 Vn6.3 conoserver_frameworkVIVII 6 5 0 3 4 — 0 Vn6.4 conoserver_frameworkVIVII 6 5 0 3 3 — 0 Vn6.5 conoserver_frameworkVIVII 6 5 0 3 6 — 0 Vn6.6 conoserver_frameworkVIVII 6 7 0 4 3 — 0 Vn6.7 conoserver_frameworkVIVII 6 7 0 4 3 — 0 Vn6.8 conoserver_frameworkVIVII 6 8 0 3 3 — 0 Vn6.9 conoserver_frameworkVIVII 6 8 0 3 3 — 0 VxVIA conoserver_frameworkVIVII 6 5 0 3 6 — 0 VxVIB conoserver_frameworkVIVII 6 8 0 3 8 — 0 conocoxin-GS conoserver_frameworkVIVII 6 3 0 4 7 — 1 ArXL4 conoserver_frameworkXI 6 5 0 3 5 — 0 Au11.6 conoserver_frameworkXI 6 5 0 3 5 — 0 BeTX conoserver_frameworkXI 6 5 0 3 4 — 0 Bt11.1 conoserver_frameworkXI 6 5 0 3 5 — 0 Bt11.4 conoserver_frameworkXI 6 5 0 3 5 — 0 Cp1.1 conoserver_frameworkXI 6 5 0 3 4 — 0 Em11.10 conoserver_frameworkXI 6 5 0 3 3 — 0 Ep11.1 conoserver_frameworkXI 6 5 0 3 3 — 0 Ep11.12 conoserver_frameworkXI 6 5 0 3 4 — 0 Fi11.11 conoserver_frameworkXI 6 5 0 3 4 — 0 Fi11.1a conoserver_frameworkXI 6 5 0 1 5 — 0 Fi11.6 conoserver_frameworkXI 6 5 0 1 5 — 0 Fi11.8 conoserver_frameworkXI 6 5 0 1 5 — 0 Im11.1 conoserver_frameworkXI 6 5 0 3 4 — 0 Im11.2 conoserver_frameworkXI 6 5 0 3 4 — 0 Im11.3 conoserver_frameworkXI 6 5 0 3 4 — 0 L11.5 conoserver_frameworkXI 6 5 0 3 5 — 0 M11.1a conoserver_frameworkXI 6 5 0 1 5 — 0 M11.2 conoserver_frameworkXI 6 5 0 3 5 — 0 M11.5 conoserver_frameworkXI 6 5 0 1 5 — 0 Mi11.1 conoserver_frameworkXI 6 5 0 3 4 — 0 R11.1 conoserver_frameworkXI 6 5 0 1 5 — 0 R11.10 conoserver_frameworkXI 6 5 0 1 5 — 0 R11.11 conoserver_frameworkXI 6 5 0 1 5 — 0 R11.12 conoserver_frameworkXI 6 5 0 1 5 — 0 R11.13 conoserver_frameworkXI 6 5 0 1 5 — 0 R11.15 conoserver_frameworkXI 6 5 0 1 5 — 0 R11.16 conoserver_frameworkXI 6 5 0 1 5 — 0 R11.17 conoserver_frameworkXI 6 5 0 1 5 — 0 R11.18 conoserver_frameworkXI 6 5 0 1 5 — 0 R11.2 conoserver_frameworkXI 6 5 0 1 5 — 0 R11.3 conoserver_frameworkXI 6 5 0 1 5 — 0 R11.5 conoserver_frameworkXI 6 5 0 1 5 — 0 R11.7 conoserver_frameworkXI 6 5 0 1 5 — 0 RXIA conoserver_frameworkXI 6 5 0 1 5 — 1 RXIB conoserver_frameworkXI 6 5 0 1 5 — 0 RXIC conoserver_frameworkXI 6 5 0 1 5 — 0 RXID conoserver_frameworkXI 6 5 0 1 5 — 0 RXIE conoserver_frameworkXI 6 5 0 3 5 — 0 RgXIA conoserver_frameworkXI 6 5 0 5 8 — 0 S11.2a conoserver_frameworkXI 6 5 0 1 5 — 0 S11.3 conoserver_frameworkXI 6 5 0 3 4 — 0 SrXIA conoserver_frameworkXI 6 5 0 3 4 — 0 Sx11.2 conoserver_frameworkXI 6 5 0 3 4 — 0 TxXI conoserver_frameworkXI 6 5 0 3 4 — 0 ViTx conoserver_frameworkXI 6 5 0 3 3 — 0 Vx11.1 conoserver_frameworkXI 6 5 0 3 3 — 0 Vx11.2 conoserver_frameworkXI 6 5 0 3 3 — 0 AVR9_CLAFU fungi1 3 5 3 2 6 — 0 U499_ASPCL fungi1 3 5 3 2 6 — 0 U499_ASPTN fungi1 3 5 3 2 4 — 0 U499_NEOFI fungi1 3 5 3 2 6 — 0 A6RPC6_BOIFB fungi2 6 6 0 4 12 — 0 A6SKI6_BOTFB fungi2 6 6 0 4 4 — 0 A7SBW4_SCLS1 fungi2 6 6 0 4 12 — 0 B0CWT3_LACBS fungi2 6 7 0 4 9 — 0 B0DIS7_LACBS fungi2 6 5 0 3 10 — 0 B0DQK7_LACBS fungi2 6 5 0 3 12 — 0 B0DQL1_LACBS fungi2 6 5 0 3 16 — 0 B0DQL3_LACBS fungi2 6 5 0 3 11 — 0 B0DUS4_LACBS fungi2 6 5 0 3 11 — 0 B0DVV7_LACBS fungi2 6 5 0 3 11 — 0 U499_CHAGB fungi2 6 5 0 4 8 — 0 U499_NSUCR fungi2 6 5 0 4 8 — 0 A0MK33 grow_factors 28 3 31 31 1 — 0 A0MK34 grow_factors 28 3 31 31 1 — 0 A0MK35 grow_factors 28 3 31 31 1 — 0 A0MK36 grow_factors 28 3 31 31 1 — 0 A0MK37 grow_factors 28 3 31 31 1 — 0 A0SLB5 grow_factors 28 3 32 31 1 — 0 A0SLB6 grow_factors 28 3 32 31 1 — 0 A1KXV9 grow_factors 28 3 31 31 1 — 0 A1XP54 grow_factors 30 3 6 33 1 — 0 A2A2V4 grow_factors 30 3 6 33 1 — 1 A2AII0 grow_factors 28 3 32 31 1 — 0 A2ARK2 grow_factors 28 3 32 31 1 — 0 A2AI03 grow_factors 28 3 32 31 1 — 0 A4UY01 grow_factors 28 3 31 31 1 — 0 A4VCG6 grow_factors 30 3 6 33 1 — 0 A5GFN1 grow_factors 28 3 32 31 1 — 0 A5GFN2 grow_factors 28 3 32 31 1 — 0 A5HMF8 grow_factors 28 3 31 31 1 — 0 A5HMF9 grow_factors 28 3 31 31 1 — 0 A5IL80 grow_factors 30 3 6 33 1 — 0 A5PII9 grow_factors 28 3 31 31 1 — 0 A6N998 grow_factors 28 3 31 31 1 — 0 A7L634 grow_factors 28 3 31 31 1 — 0 A7LCK8 grow_factors 28 3 32 31 1 — 0 A7LIT9 grow_factors 28 3 31 31 1 — 0 A7RQI0 grow_factors 28 3 32 31 1 — 0 A7SAY4 grow_factors 28 3 31 31 1 — 0 A7SZJ0 grow_factors 28 3 32 32 1 — 0 A8E7N9 grow_factors 28 3 32 31 1 — 0 A8K571 grow_factors 28 3 32 31 1 — 0 A8K694 grow_factors 28 3 32 31 1 — 0 A8S3F5 grow_factors 28 3 32 31 1 — 0 A8VIF8 grow_factors 28 3 31 31 1 — 0 A9ULK0 grow_factors 28 3 31 31 1 — 0 B0BMQ3 grow_factors 30 3 6 33 1 — 0 B0CM38 grow_factors 28 3 31 31 1 — 0 B0CM78 grow_factors 28 3 32 31 1 — 0 B0FN90 grow_factors 30 3 6 33 1 — 0 B0KWL9 grow_factors 28 3 32 31 1 — 1 B0VXV3 grow_factors 30 3 6 34 1 — 0 B0VXV4 grow_factors 30 3 6 34 1 — 0 B0WCI2 grow_factors 28 3 32 31 1 — 0 B1AKZ9 grow_factors 28 3 32 31 1 — 0 B1MTM2 grow_factors 28 3 32 31 1 — 0 B1P8C3 grow_factors 28 3 31 31 1 — 0 B2C4J5 grow_factors 30 3 6 33 1 — 0 B2C4J6 grow_factors 30 3 6 33 1 — 0 B2KI82 grow_factors 28 3 31 31 1 — 0 B2KIC7 grow_factors 28 3 32 31 1 — 0 B2KL65 grow_factors 28 3 32 31 1 — 0 B2KL66 grow_factors 28 3 32 31 1 — 0 B2RRV6 grow_factors 28 3 32 31 1 — 0 B2ZP18 grow_factors 28 3 32 31 1 — 0 B3DI86 grow_factors 28 3 31 31 1 — 0 B3DJ43 grow_factors 28 3 32 31 1 — 0 B3FNR0 grow_factors 28 3 32 31 1 — 0 B3NA13 grow_factors 28 3 32 31 1 — 0 B3RF16 grow_factors 28 3 31 31 1 — 0 B3RF47 grow_factors 28 3 32 31 1 — 0 B3Y026 grow_factors 28 3 32 31 1 — 0 B4DUF7 grow_factors 28 3 32 31 1 — 0 B4IAU3 grow_factors 28 3 32 31 1 — 0 B4KGU4 grow_factors 28 3 32 31 1 — 0 B4LUE0 grow_factors 28 3 32 31 1 — 0 B4MU02 grow_factors 28 3 32 31 1 — 0 B4NWQ1 grow_factors 28 3 32 31 1 — 0 B4QS48 grow_factors 28 3 32 31 1 — 0 B4YYD6 grow_factors 30 3 6 33 1 — 0 B5BNX6 grow_factors 28 3 32 31 1 — 0 B5BU86 grow_factors 30 3 6 33 1 — 1 B5DEK7 grow_factors 30 3 6 33 1 — 0 B5FW32 grow_factors 28 3 31 31 1 — 0 B5FW51 grow_factors 28 3 32 31 1 — 0 B5R135 grow_factors 28 3 31 31 1 — 0 B6DXF1 grow_factors 30 3 6 33 1 — 0 B6LU94 grow_factors 28 3 32 31 1 — 0 B6LUA7 grow_factors 28 3 32 31 1 — 0 B6NUD9 grow_factors 28 3 32 31 1 — 0 B6NVZ7 grow_factors 28 3 32 31 1 — 0 B6NVZ8 grow_factors 28 3 32 31 1 — 0 B6F6C2 grow_factors 28 3 32 31 1 — 0 B6SCR4 grow_factors 28 3 32 31 1 — 0 B6SCR5 grow_factors 28 3 32 31 1 — 0 B6VAE7 grow_factors 30 3 6 36 1 — 0 B6VAE8 grow_factors 30 3 6 36 1 — 0 B6ZHB6 grow_factors 28 3 32 31 1 — 0 B7NZT8 grow_factors 28 3 32 31 1 — 0 B7QHX4 grow_factors 28 3 32 31 1 — 0 B7ZPR8 grow_factors 28 3 31 31 1 — 0 B7ZQN5 grow_factors 28 3 32 31 1 — 0 B7ZRN7 grow_factors 28 3 31 31 1 — 0 B8A4Z0 grow_factors 30 3 6 33 1 — 0 B8XA45 grow_factors 28 3 31 31 1 — 0 B8XRZ3 grow_factors 28 3 31 31 1 — 0 B8YPW1 grow_factors 28 3 32 31 1 — 0 B9EI18 grow_factors 28 3 32 31 1 — 0 C0H3A5 grow_factors 28 3 31 31 1 — 0 C0K3N1 grow_factors 30 3 6 34 1 — 0 C0K3N2 grow_factors 30 3 6 34 1 — 0 C0K3N3 grow_factors 30 3 6 34 1 — 0 C0K3N4 grow_factors 30 3 6 33 1 — 0 C0K3N5 grow_factors 30 3 6 33 1 — 0 C0K3N6 grow_factors 30 3 6 34 1 — 0 C0K3N7 grow_factors 30 3 6 33 1 — 0 C0K3N8 grow_factors 30 3 6 34 1 — 0 C0K3N9 grow_factors 30 3 6 34 1 — 0 C1BJY6 grow_factors 30 3 6 33 1 — 0 C3KGR8 grow_factors 30 3 6 33 1 — 0 C3PT60 grow_factors 28 3 32 31 1 — 0 C3SB59 grow_factors 28 3 31 31 1 — 0 O13107 grow_factors 28 3 31 31 1 — 0 O13108 grow_factors 28 3 31 31 1 — 0 O13109 grow_factors 28 3 31 31 1 — 0 O19006 grow_factors 28 3 31 31 1 — 0 O42303 grow_factors 28 3 32 31 1 — 0 O42571 grow_factors 30 3 6 33 1 — 0 O42572 grow_factors 30 3 6 33 1 — 0 O46564 grow_factors 28 3 31 31 1 — 0 O46576 grow_factors 28 3 31 31 1 — 0 O57573 grow_factors 28 3 31 31 1 — 0 O57574 grow_factors 28 3 31 31 1 — 0 O73682 grow_factors 30 3 6 33 1 — 0 O73682-2 grow_factors 30 3 6 33 1 — 0 O73818 grow_factors 28 3 31 31 1 — 0 O76851 grow_factors 28 3 32 31 1 — 0 O77643 grow_factors 30 3 6 33 1 — 0 O88911 grow_factors 30 3 6 14 1 — 0 O93369 grow_factors 28 3 31 31 1 — 0 O93573 grow_factors 28 3 32 31 1 — 0 O96504 grow_factors 28 3 32 31 1 — 0 O97390 grow_factors 28 3 32 31 1 — 0 P07713 grow_factors 28 3 32 31 1 — 0 P12643 grow_factors 28 3 31 31 1 — 0 P12644 grow_factors 28 3 31 31 1 — 0 P15691 grow_factors 30 3 6 33 1 — 0 P15691-2 grow_factors 30 3 6 33 1 — 0 P15692 grow_factors 30 3 6 33 1 — 1 P15692-10 grow_factors 30 3 6 33 1 — 1 P15692-2 grow_factors 30 3 6 33 1 — 1 P15692-3 grow_factors 30 3 6 33 1 — 1 P15692-4 grow_factors 30 3 6 33 1 — 1 P15692-5 grow_factors 30 3 6 33 1 — 1 P15692-6 grow_factors 30 3 6 33 1 — 1 P15692-7 grow_factors 30 3 6 33 1 — 1 P15692-8 grow_factors 30 3 6 33 1 — 1 P15692-9 grow_factors 30 3 6 33 1 — 1 P16612 grow_factors 30 3 6 33 1 — 0 P16612-2 grow_factors 30 3 6 33 1 — 0 P16612-3 grow_factors 30 3 6 33 1 — 0 P16612-4 grow_factors 30 3 6 33 1 — 0 P18075 grow_factors 28 3 32 31 1 — 0 P20722 grow_factors 28 3 32 31 1 — 0 P21274 grow_factors 28 3 31 31 1 — 0 P21275 grow_factors 28 3 31 31 1 — 0 P22993 grow_factors 28 3 32 31 1 — 0 P22004 grow_factors 28 3 32 31 1 — 0 P23359 grow_factors 28 3 32 31 1 — 0 P25763 grow_factors 28 3 31 31 1 — 0 P26617 grow_factors 30 3 6 33 1 — 0 P30884 grow_factors 28 3 31 31 1 — 0 P30885 grow_factors 28 3 31 31 1 — 0 P35621 grow_factors 28 3 32 31 1 — 0 P43026 grow_factors 28 3 32 31 1 — 0 P43027 grow_factors 28 3 32 31 1 — 0 P43028 grow_factors 28 3 32 31 1 — 0 P43028 grow_factors 28 3 32 31 1 — 0 P43029-2 grow_factors 28 3 32 31 1 — 0 P48969 grow_factors 28 3 32 31 1 — 0 P48970 grow_factors 28 3 32 31 1 — 0 P49001 grow_factors 28 3 31 31 1 — 0 P49003 grow_factors 28 3 32 31 1 — 0 P49151 grow_factors 30 3 6 33 1 — 0 P49763 grow_factors 30 3 6 33 1 — 0 P49763-2 grow_factors 30 3 6 33 1 — 0 P49763-3 grow_factors 30 3 6 33 1 — 0 P49764 grow_factors 30 3 6 34 1 — 0 P50412 grow_factors 30 3 6 33 1 — 0 P55106 grow_factors 28 3 32 31 1 — 0 P67860 grow_factors 30 3 6 33 1 — 0 P67860-2 grow_factors 30 3 6 33 1 — 0 P67860-3 grow_factors 30 3 6 33 1 — 0 P67861 grow_factors 30 3 6 34 1 — 0 P67862 grow_factors 30 3 6 34 1 — 0 P67863 grow_factors 30 3 6 34 1 — 0 P67964 grow_factors 30 3 6 33 1 — 0 P67965 grow_factors 30 3 6 33 1 — 0 P67965-2 grow_factors 30 3 6 33 1 — 0 P67965-3 grow_factors 30 3 6 33 1 — 0 P67965-4 grow_factors 30 3 6 33 1 — 0 P82475 grow_factors 30 3 6 34 1 — 0 P83906 grow_factors 30 3 6 33 1 — 0 P83942 grow_factors 30 3 6 34 1 — 0 P85857 grow_factors 30 3 32 31 1 — 0 P87373 grow_factors 28 3 32 31 1 — 0 P91706 grow_factors 28 3 32 31 1 — 0 P91720 grow_factors 28 3 32 31 1 — 0 Q00731 grow_factors 30 3 6 33 1 — 0 Q00731-2 grow_factors 30 3 6 33 1 — 0 Q00731-3 grow_factors 30 3 6 33 1 — 0 Q00731-4 grow_factors 30 3 6 40 1 — 0 Q04906 grow_factors 28 3 32 31 1 — 0 Q66826 grow_factors 28 3 31 31 1 — 0 Q07081 grow_factors 30 3 6 33 1 — 0 Q0P6N0 grow_factors 28 3 31 33 1 — 0 Q0QYI0 grow_factors 30 3 6 33 1 — 0 Q17JZ3 grow_factors 28 3 32 31 1 — 0 Q15I09 grow_factors 30 3 6 33 1 — 0 Q1ANE8 grow_factors 30 3 6 33 1 — 0 Q1ECU5 grow_factors 30 3 6 33 1 — 0 Q1PHR6 grow_factors 28 3 32 33 1 — 0 Q1PHR7 grow_factors 28 3 32 31 1 — 0 Q1WEY6 grow_factors 28 3 32 31 1 — 0 Q1WKY7 grow_factors 28 3 32 31 1 — 0 Q1WKY8 grow_factors 28 3 32 31 1 — 0 Q15211 grow_factors 28 3 32 31 1 — 0 Q26468 grow_factors 28 3 32 31 1 — 0 Q27W10 grow_factors 28 3 32 31 1 — 0 Q29607 grow_factors 28 3 31 31 1 — 0 Q35H1 grow_factors 28 3 31 31 1 — 0 Q2KT33 grow_factors 28 3 31 31 1 — 0 Q2NKW7 grow_factors 28 3 32 31 1 — 0 Q2VEW5 grow_factors 28 3 31 31 1 — 0 Q2WBX0 grow_factors 28 3 32 31 1 — 0 Q330H7 grow_factors 28 3 33 31 1 — 0 Q330K6 grow_factors 30 3 6 34 1 — 0 Q38KY2 grow_factors 30 3 6 33 1 — 0 QHSL9 grow_factors 28 3 32 31 1 — 0 QHSM3 grow_factors 28 3 32 31 1 — 0 Q3ULR1 grow_factors 28 3 31 31 1 — 0 Q3UXB2 grow_factors 28 3 32 31 1 — 0 Q3VIM grow_factors 28 3 31 31 1 — 0 Q496PS grow_factors 28 3 32 31 1 — 0 Q496P9 grow_factors 28 3 31 31 1 — 0 Q497W8 grow_factors 28 3 32 31 1 — 0 Q4H2P7 grow_factors 28 3 32 31 1 — 0 Q4ICQ2 grow_factors 28 3 32 31 1 — 0 QNLEV0 grow_factors 28 3 31 31 1 — 0 Q4R5W6 grow_factors 28 3 32 31 1 — 0 Q4RLYS grow_factors 30 3 6 34 1 — 0 Q4RMK1 grow_factors 28 3 31 31 1 — 0 Q4RQB0 grow_factors 28 3 32 31 1 — 0 Q4SCW7 grow_factors 30 3 6 34 1 — 0 Q4SSW6 grow_factors 28 3 32 31 1 — 0 Q4SV40 grow_factors 30 3 6 33 1 — 0 Q4SZ19 grow_factors 28 3 32 33 1 — 0 Q4U4G1 grow_factors 30 3 6 33 1 — 0 Q4VBA3 grow_factors 28 3 32 31 1 — 0 Q53XC5 grow_factors 28 3 31 31 1 — 0 Q53XY6 grow_factors 30 3 6 33 1 — 0 Q540I2 grow_factors 30 3 6 33 1 — 0 Q541S7 grow_factors 30 3 6 33 1 — 0 Q544A5 grow_factors 30 3 6 34 1 — 0 Q58E94 grow_factors 28 3 31 31 1 — 0 Q58G88 grow_factors 28 3 32 31 1 — 0 Q58FH5 grow_factors 30 3 6 33 1 — 1 Q5I4I9 grow_factors 28 3 31 31 1 — 0 Q5RHW5 grow_factors 30 3 6 33 1 — 0 Q5RKN7 grow_factors 28 3 32 31 1 — 0 Q5YJC3 grow_factors 28 3 32 32 1 — 0 Q63434 grow_factors 30 3 6 34 1 — 0 Q64FZ6 grow_factors 30 3 6 33 1 — 0 Q66KL4 grow_factors 28 3 32 31 1 — 0 Q68KG0 grow_factors 28 3 32 31 1 — 0 Q6AYU9 grow_factors 28 3 31 31 1 — 0 Q6EH35 grow_factors 28 3 31 31 1 — 0 Q6H8S7 grow_factors 30 3 6 33 1 — 0 Q6H8S8 grow_factors 30 3 6 33 1 — 0 Q6HA10 grow_factors 28 3 32 31 1 — 0 Q6J384 grow_factors 28 3 31 31 1 — 0 Q6J385 grow_factors 28 3 31 31 1 — 0 Q6J386 grow_factors 28 3 31 31 1 — 0 Q6J936 grow_factors 30 3 6 34 1 — 0 Q6KF10 grow_factors 28 3 32 31 1 — 0 Q6P4J4 grow_factors 28 3 32 31 1 — 0 Q6PAF3 grow_factors 28 3 31 31 1 — 0 Q6R5A5 grow_factors 30 3 6 45 1 — 0 Q6RF65 grow_factors 28 3 31 31 1 — 0 Q6TVT2 grow_factors 30 3 6 41 1 — 0 Q6WZM0 grow_factors 30 3 6 37 1 — 0 Q6XDQ0 grow_factors 28 3 31 31 1 — 0 Q6YLN3 grow_factors 30 3 6 33 1 — 0 Q75N54 grow_factors 28 3 31 31 1 — 0 Q75RY1 grow_factors 28 3 32 31 1 — 0 Q72WK6 grow_factors 28 3 32 31 1 — 0 Q772M8 grow_factors 30 3 6 33 1 — 0 Q7SDH3 grow_factors 28 3 31 31 1 — 0 Q78DH4 grow_factors 28 3 31 31 1 — 0 Q72DH5 grow_factors 28 3 31 31 1 — 0 Q78DH6 grow_factors 28 3 31 31 1 — 0 Q7Q3Q7 grow_factors 28 3 32 31 1 — 0 Q7T2S8 grow_factors 28 3 32 31 1 — 0 Q7Z4P5 grow_factors 28 3 32 31 1 — 0 Q80482 grow_factors 28 3 31 31 1 — 0 Q80482 grow_factors 28 3 31 31 1 — 0 Q811S3 grow_factors 28 3 31 31 1 — 0 Q866G4 grow_factors 30 3 6 33 1 — 0 Q869A4 grow_factors 28 3 32 31 1 — 0 Q86RL7 grow_factors 28 3 32 31 1 — 0 Q80RW3 grow_factors 28 3 32 31 1 — 0 Q8HRW9 grow_factors 28 3 32 31 1 — 0 Q8CCE0 grow_factors 28 3 32 31 1 — 0 Q8HY70 grow_factors 30 3 6 33 1 — 0 Q8HY75 grow_factors 30 3 6 33 1 — 0 Q8IAE3 grow_factors 28 3 32 31 1 — 0 Q8IFE2 grow_factors 28 3 31 31 1 — 0 Q8JIJ2 grow_factors 28 3 31 31 1 — 0 Q8JIJ3 grow_factors 28 3 31 31 1 — 0 Q8JIJ4 grow_factors 28 3 31 31 1 — 0 Q8JIJ5 grow_factors 28 3 31 31 1 — 0 Q8JIJ6 grow_factors 28 3 31 31 1 — 0 Q8JIJ7 grow_factors 28 3 31 31 1 — 0 Q8JIJ8 grow_factors 28 3 31 31 1 — 0 Q8JIJ9 grow_factors 28 3 31 31 1 — 0 Q8JIK0 grow_factors 28 3 31 31 1 — 0 Q8JIK1 grow_factors 28 3 31 31 1 — 0 Q8JIK2 grow_factors 28 3 31 31 1 — 0 Q8MJV5 grow_factors 28 3 31 31 1 — 0 Q8MWG4 grow_factors 28 3 32 31 1 — 0 Q8MXC2 grow_factors 28 3 32 31 1 — 0 Q8MXZ3 grow_factors 28 3 32 31 1 — 0 Q8SPL5 grow_factors 20 3 6 33 1 — 0 Q8SPZ9 grow_factors 30 3 6 33 1 — 0 Q8WMQ4 grow_factors 30 3 6 33 1 — 0 Q8WS99 grow_factors 28 3 32 31 1 — 0 Q90723 grow_factors 28 3 32 31 1 — 0 Q90751 grow_factors 28 3 31 31 1 — 0 Q90752 grow_factors 28 3 31 31 1 — 0 Q90X23 grow_factors 30 3 6 34 1 — 0 Q90X24 grow_factors 30 3 6 34 1 — 0 Q90Y81 grow_factors 28 3 31 31 1 — 0 Q90Y82 grow_factors 28 3 31 31 1 — 0 Q90YD6 grow_factors 28 3 31 31 1 — 0 Q90YD7 grow_factors 28 3 31 31 1 — 0 Q91403 grow_factors 28 3 32 31 1 — 0 Q91703 grow_factors 28 3 31 31 1 — 0 Q95LQ4 grow_factors 30 3 6 33 1 — 0 Q95NE5 grow_factors 30 3 6 33 1 — 1 Q95W38 grow_factors 28 3 32 31 1 — 0 Q98P50 grow_factors 28 3 32 31 1 — 0 Q99PS1 grow_factors 30 3 6 33 1 — 0 Q9BDP7 grow_factors 30 3 6 33 1 — 1 Q9BDW8 grow_factors 28 3 32 31 1 — 0 Q9BDW9 grow_factors 28 3 32 31 1 — 0 Q9DGN4 grow_factors 28 3 32 31 1 — 0 Q9BRL6 grow_factors 30 3 6 33 1 — 0 Q9GK00 grow_factors 30 3 6 33 1 — 0 Q9CKR0 grow_factors 30 3 6 33 1 — 0 Q98T6 grow_factors 28 3 32 31 1 — 0 Q9MYV3 grow_factors 30 3 6 33 1 — 0 Q9MYV3-2 grow_factors 30 3 6 33 1 — 0 Q9MYV3-3 grow_factors 30 3 6 32 1 — 0 Q9MZB1 grow_factors 30 3 6 33 1 — 0 Q9MZV5 grow_factors 28 3 31 31 1 — 0 Q9PTF9 grow_factors 28 3 32 31 1 — 0 Q9QX39 grow_factors 30 3 6 33 1 — 0 Q9U418 grow_factors 28 3 32 31 1 — 0 Q9U5E8 grow_factors 28 3 32 31 1 — 0 Q9W8C0 grow_factors 28 3 32 31 1 — 0 Q9W6G0 grow_factors 28 3 32 31 1 — 0 Q9W753 grow_factors 28 3 32 31 1 — 0 Q9XS47 grow_factors 30 3 6 33 1 — 0 Q9XYQ7 grow_factors 28 3 32 31 1 — 0 Q9XYQ8 grow_factors 28 3 32 31 1 — 0 Q9XZ69 grow_factors 28 3 32 31 1 — 0 Q9YGH7 grow_factors 28 3 32 31 1 — 0 Q9YGV1 grow_factors 28 3 32 31 1 — 0 Q9YMF3 grow_factors 30 3 6 33 1 — 0 GUR_GYM3Y

6 6 0 4 9 — 2 ALO1_ACRLO insect_antimicrobial 6 8 0 3 10 — 0 ALO2_ACRLO insect_antimicrobial 6 8 0 3 10 — 0 ALO3_ACRLO insect_antimicrobial 6 8 0 3 10 — 1 CVP3_PIMHY insect_antimicrobial 6 5 0 4 9 — 0 CVP5_PIMHY insect_antimicrobial 6 8 0 2 6 — 0 Q2MJU0_LYSTE insect_antimicrobial 6 5 0 6 6 — 0 Q2PQC7_BEMTA insect_antimicrobial 6 8 0 3 11 — 0 Q2PQC8_BEMTA insect_antimicrobial 6 8 0 3 10 — 0 Q2PQC9_BEMTA insect_antimicrobial 6 8 0 3 14 — 0 Q2PQD0_BEMTA insect_antimicrobial 6 8 0 3 12 — 0 Q3LTD6_9DRT insect_antimicrobial 6 8 0 3 10 — 0 FSPM_SOLLC metallocarboxypeptidase_inhibitor 3 5 5 2 13 — 0 MCPI_SOLLC metallocarboxypeptidase_inhibitor 3 5 5 2 6 — 0 MCPI_SOLTU metallocarboxypeptidase_inhibitor 3 5 5 2 6 — 2 O24372_SOLTU metallocarboxypeptidase_inhibitor 3 5 5 2 13 — 0 O24373_SOLTU metallocarboxypeptidase_inhibitor 3 5 5 2 13 — 0 O24639_SOLTU metallocarboxypeptidase_inhibitor 3 5 5 2 13 — 0 Q38480_SOLTU metallocarboxypeptidase_inhibitor 3 5 5 2 13 — 0 Q38486_SOLTU metallocarboxypeptidase_inhibitor 3 5 5 2 13 — 0 Q41432_SOLTU metallocarboxypeptidase_inhibitor 3 5 5 2 13 — 0 Q948ZS_SOLTU metallocarboxypeptidase_inhibitor 3 5 5 2 13 — 0 Q949A1_SOLBR metallocarboxypeptidase_inhibitor 3 5 5 2 14 — 0 Q9SEH8_SOLTU metallocarboxypeptidase_inhibitor 3 5 5 2 6 — 0 Q9SXP0_HYONI metallocarboxypeptidase_inhibitor 3 5 5 2 11 — 0 POI_MUSDO phenoloxidase_inhibitor 6 5 0 3 6 — 0 Q170Q5_AEDAE phenoloxidase_inhibitor 6 5 0 3 6 — 0 Q170Q6_AEDAE phenoloxidase_inhibitor 6 5 0 3 6 — 0 Q5BN34_ANOGA phenoloxidase_inhibitor 6 5 0 3 6 — 0 AMP1_MESCR plant_antimicrobial 6 8 0 3 10 — 0 AMP1_MIRIA plant_antimicrobial 6 8 0 3 10 — 0 AMP2_MIRIA plant_antimicrobial 6 8 0 3 10 — 0 PAFP_PHYAM plant_antimicrobial 6 8 0 3 10 — 1 Q54A12_PHYAM plant_antimicrobial 6 8 0 3 10 — 0 Q9SDS1_PHYAM plant_antimicrobial 6 8 0 3 10 — 0 DEF1_PETHY plant_defensia 6 5 2 10 6 — 1 DEF2_PETHY plant_defensia 6 5 2 12 6 — 0 ALB1A_PEA plant_toxin 3 7 4 1 9 — 0 ALB1B_PEA plant_toxin 3 7 4 1 9 — 1 ALB1C_PEA plant_toxin 3 7 4 1 8 — 0 ALB1D_PEA plant_toxin 3 7 4 1 9 — 0 ALB1E_PEA plant_toxin 3 7 4 1 9 — 0 ALB1F_PEA plant_toxin 3 7 4 1 9 — 0 ALB1_GLYSO plant_toxin 3 7 4 1 9 — 0 ALB1_PHAAN plant_toxin 3 7 4 1 10 — 0 ALB1_PHAAU plant_toxin 3 7 4 1 9 — 0 ALB2_SOYBN plant_toxin 3 7 4 1 9 — 1 O24095_MEDTR plant_toxin 6 7 4 1 11 — 0 O24100_MEDTR plant_toxin 6 7 5 1 9 — 0 O48617_MEDTR plant_toxin 6 7 5 1 11 — 0 Q6A1C7_9FABA plant_toxin 3 7 4 1 9 — 0 Q6A1C8_TRIFG plant_toxin 3 7 4 1 9 — 0 Q6A1C9_ONOVI plant_toxin 3 7 4 1 9 — 0 Q6A1D1_9FABA plant_toxin 5 7 5 1 9 — 0 Q6A1D2_MELAB plant_toxin 3 7 4 1 9 — 0 Q6A1D3_LONCA plant_toxin 5 7 5 1 9 — 0 Q6A1D4_CANBR plant_toxin 3 7 4 1 9 — 0 Q6A1D5_9FABA plant_toxin 3 7 4 1 9 — 0 Q6A1D6_9FABA plant_toxin 3 7 4 1 9 — 0 Q6A1D7_9FABA plant_toxin 3 7 4 1 9 — 0 Q7XZC2_PHAVU plant_toxin 3 7 5 1 9 — 0 Q7XZC3_SOYBN plant_toxin 3 7 4 1 9 — 0 Q7XZC3_MEDTR plant_toxin 3 7 4 1 9 — 0 SOCT_MESMA scorpica1 2 10 2 6 4 — 0 SOCX_MESMA scorpica1 2 10 2 6 4 — 0 SCTT_MESTA scorpica1 2 10 2 7 4 — 0 SCX1_BUTEU scorpica1 2 10 2 6 4 — 0 SCX1_BUTSI scorpica1 2 10 2 8 4 — 0 SCX1_LEIQH scorpica1 2 10 2 6 4 — 0 SCX3_BUTEU scorpica1 2 10 2 7 3 — 0 SCX3_MESTA scorpica1 2 10 2 6 4 — 0 SCX4_BUTEU scorpica1 2 10 2 6 4 — 0 SCX5_BUTEU scorpica1 2 10 2 6 4 — 1 SCX8_LEIQH scorpica1 2 10 2 8 4 — 0 SCXL_BUTSI scorpica1 2 10 2 6 4 — 0 SCXL_LEIQU scorpica1 2 10 2 8 4 — 1 SCXT_ANDMA scorpica1 2 10 2 6 4 — 0 SCX8_BUTEU scorpica1 2 10 2 6 4 — 0 IPIXA_PANIM scorpica2 6 5 0 3 10 — 1 SCX1_OPICA scorpica2 6 5 0 3 10 — 0 SCX2_OPICA scorpica2 6 5 0 3 10 — 0 SCXC1_MESMA scorpica2 6 5 0 5 8 — 0 SCXC_SCOMA scorpica2 6 5 0 3 10 — 1 KGX11_CENNO scorpica3 5 8 2 10 4 — 2 KGX12_CENEL scorpica3 5 8 2 10 4 — 0 KGX13_CENGR scorpica3 5 8 2 10 4 — 0 KGX14_CENSC scorpica3 5 8 2 10 4 — 0 KGX15_CENLL scorpica3 5 8 2 10 4 — 0 KGX16_CENEX scorpica3 5 8 2 10 4 — 0 KGX31_CENNO scorpica3 5 8 2 10 4 — 0 KGX32_CENEL scorpica3 5 8 2 10 4 — 0 KGX33_CENSC scorpica3 5 8 2 10 4 — 0 KGX34_CENGR scorpica3 5 8 2 10 4 — 0 KGX41_CENLL scorpica3 5 8 2 10 4 — 0 KGX42_CENNO scorpica3 5 8 2 10 4 — 0 KGX43_CENEX scorpica3 5 8 2 10 4 — 0 KGX44_CENEX scorpica3 5 8 2 10 4 — 0 KGX45_CENEX scorpica3 5 8 2 10 4 — 0 KGX46_CENLL scorpica3 5 8 2 10 4 — 0 KGX47_CENLL scorpica3 5 8 2 10 4 — 0 KGX48_CENEL scorpica3 5 8 2 10 4 — 0 KGX49_CENSC scorpica3 5 8 2 10 4 — 0 KGX4A_CENSC scorpica3 5 8 2 10 4 — 0 KGX4B_CENNO scorpica3 5 8 2 10 4 — 0 KGX4C_CENSC scorpica3 5 8 2 10 4 — 0 KGX4D_CENNO scorpica3 5 8 2 10 4 — 0 KGX52_CENSC scorpica3 5 8 2 10 4 — 0 KGX52_CENGR scorpica3 5 8 2 10 4 — 0 A6N2U8_MOMCH serine_proteinase_inhib 6 5 3 1 4 — 0 ISLI_MOMCH serine_proteinase_inhib 6 5 3 1 4 — 0 ITH_LAGCE serine_proteinase_inhib 6 5 3 1 3 — 0 ITR1_CITLA serine_proteinase_inhib 6 5 3 1 5 — 0 ITR1_CUCMA serine_proteinase_inhib 6 5 3 1 5 — 7 ITR1_LUFCY serine_proteinase_inhib 6 5 3 1 5 — 0 ITR1_MOMCH serine_proteinase_inhib 6 5 3 1 5 — 0 ITR1_MOMCO serine_proteinase_inhib 6 5 3 1 5 — 0 ITR1_MOMRE serine_proteinase_inhib 6 5 3 1 5 — 0 ITR1_TRIKJ serine_proteinase_inhib 6 5 3 1 5 — 0 ITR2B_CUCSA serine_proteinase_inhib 6 5 3 1 6 — 0 ITR2_ERYDI serine_proteinase_inhib 6 5 3 1 5 — 0 ITR2_ECBEL serine_proteinase_inhib 6 5 3 1 5 — 7 ITR2_LUFCY serine_proteinase_inhib 6 5 3 1 6 — 0 ITR2_MOMCH serine_proteinase_inhib 6 5 3 1 4 — 1 ITR2_MOMCO serine_proteinase_inhib 6 5 3 1 5 — 3 ITR2_SECED serine_proteinase_inhib 6 5 3 1 3 — 0 ITR3_CUCMC serine_proteinase_inhib 6 5 3 1 5 — 0 ITR3_CUCPE serine_proteinase_inhib 6 5 3 1 5 — 2 ITR3_CYCPE serine_proteinase_inhib 6 5 3 1 5 — 0 ITR3_LUFCY serine_proteinase_inhib 6 5 3 1 5 — 0 ITR3_MOMCH serine_proteinase_inhib 6 5 3 1 5 — 0 ITR3_MOMCO serine_proteinase_inhib 6 5 3 1 5 — 0 ITR4_CUCMA serine_proteinase_inhib 6 5 3 1 5 — 0 ITR4_CUCSA serine_proteinase_inhib 6 5 3 1 6 — 0 ITR4_CYCPE serine_proteinase_inhib 6 5 3 1 6 — 0 ITR4_LUFCY serine_proteinase_inhib 6 5 3 1 6 — 0 ITR5_CYCPE serine_proteinase_inhib 6 5 3 1 6 — 0 ITR5_LUFCY serine_proteinase_inhib 6 5 3 1 6 — 0 ITR5_SECED serine_proteinase_inhib 6 5 3 1 6 — 0 ITR6_CYCPE serine_proteinase_inhib 6 5 3 1 6 — 0 ITR7_CYCPE serine_proteinase_inhib 6 5 3 1 6 — 0 ITRA_MOMCH serine_proteinase_inhib 6 5 3 1 4 — 1 Q9S8D2_CUCME serine_proteinase_inhib 6 5 3 1 5 — 0 Q9S8W2_CUCME serine_proteinase_inhib 6 5 3 1 5 — 0 Q9S8W3_CUCME serine_proteinase_inhib 6 5 3 1 5 — 0 ITR1_MIRIA serine_proteinase_inhib_2 6 7 0 3 10 — 0 ITR1_SPIOL serine_proteinase_inhib_2 6 8 0 3 10 — 0 ITR2_SPIOL serine_proteinase_inhib_2 6 8 0 3 10 — 0 ITR3_SPIOL serine_proteinase_inhib_2 6 8 0 3 10 — 0 29C0_ANCSP spider 5 4 0 10 9 — 0 A5A3H0_ATRRO spider 6 5 0 3 13 — 0 A5A3H1_ATRRO spider 6 5 0 3 13 — 0 A5A3H3_ATRRO spider 6 5 0 3 13 — 0 A5A3H4_ATRRO spider 6 5 0 3 13 — 0 A5A3H5_ATRRO spider 6 5 0 3 13 — 0 A9XDF9_GEOA2 spider 6 6 0 4 19 — 0 A9XDG0_GEOA2 spider 6 6 0 4 19 — 0 A9XDG1_GEOA2 spider 6 6 0 4 19 — 0 A9XDG2_GEOA2 spider 6 6 0 4 19 — 0 A9XDG3_GEOA2 spider 6 6 0 4 19 — 0 A9XDG4_GEOA2 spider 6 6 0 4 19 — 0 A9XDG5_GEOA2 spider 6 6 0 4 19 — 0 AF1_GRARO spider 6 5 0 4 3 — 0 AF2_GRARO spider 6 5 0 4 3 — 0 B1P1A0_CHIJI spider 6 5 0 4 6 — 0 B1P1A1_CHIJI spider 6 6 0 4 6 — 0 B1P1A2_CHIJI spider 6 5 0 4 7 — 0 B1P1A3_CHIJI spider 6 6 0 4 6 — 0 B1P1A4_CHIJI spider 6 6 0 4 6 — 0 B1P1B0_CHIJI spider 6 5 0 4 9 — 0 B1P1B1_CHIJI spider 6 5 0 4 9 — 0 B1P1B2_CHIJI spider 6 5 0 4 9 — 0 B1P1B3_CHIJI spider 6 5 0 4 9 — 0 B1P1B4_CHIJI spider 6 7 0 2 4 — 0 B1P1B5_CHIJI spider 6 5 0 4 3 — 0 B1P1B6_CHIJI spider 6 5 0 4 3 — 0 B1P1B7_CHIJI spider 6 6 0 4 6 — 0 B1P1B8_CHIJI spider 6 6 0 4 6 — 0 B1P1B9_CHIJI spider 6 5 0 4 6 — 0 B1P1C0_CHIJI spider 6 6 0 4 6 — 0 B1P1C1_CHIJI spider 6 6 0 4 6 — 0 B1P1C2_CHIJI spider 6 6 0 4 6 — 0 B1P1C3_CHIJI spider 6 6 0 4 6 — 0 B1P1C4_CHIJI spider 6 6 0 4 6 — 0 B1P1C6_CHIJI spider 6 6 0 4 6 — 0 B1P1C8_CHIJI spider 6 6 0 4 6 — 0 B1P1C9_CHIJI spider 6 6 0 4 6 — 0 B1P1D0_CHIJI spider 6 6 0 4 6 — 0 B1P1D1_CHIJI spider 6 5 0 4 6 — 0 B1P1D2_CHIJI spider 6 5 0 4 6 — 0 B1P1D3_CHIJI spider 6 5 0 4 6 — 0 B1P1D4_CHIJI spider 6 5 0 4 6 — 0 B1P1D5_CHIJI spider 6 6 0 4 6 — 0 B1P1D6_CHIJI spider 6 6 0 4 6 — 0 B1P1D7_CHIJI spider 6 5 0 4 6 — 0 B1P1D8_CHIJI spider 6 5 0 4 6 — 0 B1P1D9_CHIJI spider 6 5 0 4 6 — 0 B1P1E0_CHIJI spider 6 5 0 4 6 — 0 B1P1E1_CHIJI spider 6 5 0 4 6 — 0 B1P1E2_CHIJI spider 6 5 0 4 6 — 0 B1P1E3_CHIJI spider 6 5 0 4 6 — 0 B1P1E4_CHIJI spider 6 5 0 4 6 — 0 B1P1E5_CHIJI spider 6 5 0 4 5 — 0 B1P1E6_CHIJI spider 6 5 0 4 5 — 0 B1P1E7_CHIJI spider 6 5 0 4 6 — 0 B1P1E8_CHIJI spider 6 5 0 4 5 — 0 B1P1F0_CHIJI spider 6 6 0 4 5 — 0 B1P1F1_CHIJI spider 6 6 0 4 6 — 0 B1P1F2_CHIJI spider 6 6 0 4 6 — 0 B1P1F3_CHIJI spider 6 5 0 4 6 — 0 B1P1F4_CHIJI spider 6 5 0 4 6 — 0 B1P1F5_CHIJI spider 6 5 0 4 7 — 0 B1P1F6_CHIJI spider 6 5 0 4 7 — 0 B1P1F7_CHIJI spider 6 5 0 4 7 — 0 B1P1F8_CHIJI spider 6 5 0 4 7 — 0 B1P1F9_CHIJI spider 6 5 0 4 7 — 0 B1P1G0_CHIJI spider 6 5 0 4 7 — 0 B1P1G2_CHIJI spider 6 5 0 4 7 — 0 B1P1G3_CHIJI spider 6 5 0 4 7 — 0 B1P1G4_CHIJI spider 6 5 0 4 7 — 0 B1P1G5_CHIJI spider 6 5 0 4 7 — 0 B1P1G6_CHIJI spider 6 5 0 4 7 — 0 B1P1G7_CHIJI spider 6 5 0 4 7 — 0 B1P1G8_CHIJI spider 6 5 0 4 6 — 0 B1P1G9_CHIJI spider 6 5 0 4 5 — 0 B1P1H0_CHIJI spider 6 5 0 4 5 — 0 B1P1H1_CHIJI spider 6 5 0 4 6 — 0 B1P1H2_CHIJI spider 6 6 0 4 6 — 0 B1P1H3_CHIJI spider 6 7 0 4 9 — 0 B1P1H4_CHIJI spider 6 7 0 4 9 — 0 B1P1H5_CHIJI spider 6 7 0 4 9 — 0 B1P1H6_CHIJI spider 6 6 0 4 14 — 0 B1P1H7_CHIJI spider 6 6 0 4 14 — 0 B1P1H8_CHIJI spider 6 9 0 4 4 — 0 B1P1H9_CHIJI spider 6 5 0 4 7 — 0 B1P1I0_CHIJI spider 6 5 0 10 8 — 0 CALA_CALS5 spider 6 5 0 3 16 — 0 CALB_CALS5 spider 6 5 0 3 16 — 0 CALC_CALS5 spider 6 5 0 3 16 — 0 F256_OLIOR spider 6 5 0 3 8 — 0 JZT11_CHIJI spider 6 5 0 4 6 — 0 JZT12_CHIJI spider 6 5 0 4 3 — 0 JZTX1_CHIJI spider 6 6 0 4 6 — 0 JZTX3_CHIJI spider 6 6 0 4 6 — 1 JZTX5_CHIJI spider 6 5 0 4 3 — 0 JZTX7_CHIJI spider 6 6 0 4 6 — 2 MTX2_GRARO spider 6 5 0 4 3 — 1 MTX4_GRARO spider 6 6 0 5 6 — 2 Q5Y4U5_AGEOR spider 6 4 0 4 8 — 0 Q5Y4U6_AGEOR spider 6 8 0 4 9 — 0 Q5Y4U7_AGEOR spider 6 6 0 4 9 — 0 Q5Y4U8_AGEOR spider 6 7 0 4 8 — 0 Q5Y4U9_AGEOR spider 6 7 0 4 9 — 0 Q5Y4V0_AGEOR spider 6 7 0 4 9 — 0 Q5Y4V1_AGEOR spider 6 7 0 4 9 — 0 Q5Y4V2_AGEOR spider 6 7 0 4 9 — 0 Q5Y4V3_AGEOR spider 6 7 0 4 9 — 0 Q5Y4V4_AGEOR spider 6 7 0 4 9 — 0 Q5Y4V5_AGEOR spider 6 7 0 4 9 — 0 Q5Y4V6_AGEOR spider 6 7 0 4 8 — 0 Q5Y4V7_AGEOR spider 6 7 0 4 9 — 0 Q5Y4V8_AGEOR spider 6 7 0 4 9 — 0 Q5Y4W0_AGEOR spider 4 5 0 4 10 — 0 Q5Y4W1_AGEOR spider 6 7 0 4 9 — 0 Q5Y4W2_AGEOR spider 6 7 0 4 9 — 0 Q5Y4W3_AGEOR spider 6 7 0 4 9 — 0 Q5Y4W4_AGEOR spider 6 7 0 4 9 — 0 Q5Y4W5_AGEOR spider 6 7 0 4 8 — 0 Q5Y4W6_AGEOR spider 6 7 0 4 9 — 0 Q5Y4W7_AGEOR spider 6 7 0 4 9 — 0 Q5Y4W8_AGEOR spider 6 7 0 4 9 — 0 Q5Y4X0_AGEOR spider 6 7 0 4 9 — 0 Q5Y4X1_AGEOR spider 6 7 0 4 9 — 0 Q5Y4X2_AGEOR spider 6 7 0 4 9 — 0 Q5Y4X3_AGEOR spider 6 7 0 4 9 — 0 Q5Y4X4_AGEOR spider 6 7 0 4 9 — 0 Q5Y4X6_AGEOR spider 6 7 0 4 9 — 0 Q5Y4Y0_AGEOR spider 6 7 0 4 9 — 0 Q5Y4Y1_AGEOR spider 6 7 0 4 9 — 0 Q5Y4Y2_AGEOR spider 6 7 0 4 9 — 0 Q5Y4Y4_AGEOR spider 6 7 0 4 9 — 0 SFI1_SEGFL spider 6 7 0 4 17 — 0 SFI2_SEGFL spider 6 7 0 4 17 — 0 SFI3_SEGFL spider 6 7 0 4 17 — 0 SFI4_SEGFL spider 6 7 0 4 17 — 0 SFI5_SEGFL spider 6 7 0 4 17 — 0 SFI6_SEGFL spider 6 7 0 4 17 — 0 SFI7_SEGFL spider 6 7 0 4 17 — 0 SFI8_SEGFL spider 6 7 0 4 17 — 0 T244_PHONI spider 6 5 0 3 8 — 0 TACHC_TACTR spider 6 7 0 4 4 — 0 TJT1A_HADFO spider 6 5 0 4 10 — 0 TJT1A_HADVE spider 6 5 0 4 10 — 0 TJT1B_HADVE spider 6 5 0 4 10 — 0 TJT1C_HADVE spider 6 5 0 4 9 — 1 TOG4A_AGEAP spider 7 6 0 4 10 — 3 TOG4B_AGEAP spider 7 6 0 4 10 — 3 TONGA_MISBR spider 6 6 0 10 7 — 0 TOT1A_ATRRG spider 6 5 0 3 13 — 0 TOT1A_HADIN spider 6 5 0 3 13 — 0 TOT1A_HADVE spider 6 5 0 3 13 — 2 TOT1B_HADFO spider 6 5 0 3 13 — 0 TOT1B_HADIN spider 6 5 0 3 13 — 0 TOT1B_HADVE spider 6 5 0 3 13 — 0 TOT1C_HADIN spider 6 5 0 3 13 — 0 TOT1C_HADVE spider 6 5 0 3 13 — 0 TOT1D_HADVE spider 6 5 0 3 13 — 0 TOT1E_HADVE spider 6 5 0 3 13 — 0 TOT1F_HADVE spider 6 5 0 3 13 — 0 TOT2A_ATRIL spider 5 5 0 5 4 — 0 TOT2A_HADIN spider 6 5 0 5 4 — 0 TOT2A_HADVE spider 6 5 0 5 4 — 2 TOT2B_ATRIL spider 5 5 0 5 4 — 0 TOT2B_HADIN spider 6 5 0 5 4 — 0 TX13_CUPSA spider 6 6 0 8 14 — 0 TX13_PHONI spider 6 5 0 3 8 — 0 TX17_PHORI spider 6 5 0 3 8 — 0 TX19_PHOKE spider 6 4 0 8 8 — 0 TX1A_GEOA2 spider 6 6 0 4 19 — 0 TX1_CERCR spider 6 6 0 4 6 — 0 TX1_GRARO spider 6 5 0 4 3 — 0 TX1_HETMC spider 6 5 0 4 6 — 0 TX1_PSACA spider 6 5 0 4 6 — 0 TX1_SCOGR spider 6 5 0 4 6 — 1 TX1_STRCF spider 6 5 0 4 6 — 0 TX1_THEBL spider 6 6 0 4 6 — 0 TX21_PHOKE spider 6 5 0 3 8 — 0 TX22_PHOKE spider 6 6 0 4 13 — 0 TX22_PHONI spider 6 5 0 4 9 — 0 TX24_PHONI spider 6 5 0 3 8 — 0 TX27_PHONI spider 6 5 0 4 11 — 0 TX27_PHORI spider 6 5 0 4 11 — 0 TX29_PHONI spider 5 5 0 4 8 — 0 TX2_CERCR spider 6 6 0 4 6 — 0 TX2_HETMC spider 6 5 0 4 10 — 0 TX2_PSACA spider 6 5 0 4 6 — 0 TX2_THEBL spider 6 6 0 4 6 — 0 TX31_PHONI spider 6 6 0 4 10 — 0 TX325_SEGFL spider 6 10 0 4 20 — 0 TX32_PHOKE spider 6 5 0 4 11 — 0 TX32_PHONI spider 6 6 0 4 10 — 0 TX33A_PHONI spider 6 5 0 9 8 — 0 TX35A_PHONI spider 6 6 0 4 13 — 0 TX35_PHONI spider 6 6 0 4 16 — 0 TX37_PHORI spider 6 6 0 4 10 — 0 TX3A_PHONI spider 6 6 0 4 9 — 0 TX3_CERCR spider 6 5 0 4 6 — 0 TX3_LOXIN spider 6 9 0 15 10 — 0 TX3_PARSR spider 6 6 0 5 6 — 0 TX3_PSACA spider 6 5 0 4 6 — 0 TX3_THEBL spider 6 6 0 4 6 — 0 TX432_HYSGI spider 6 5 0 4 6 — 0 TX5A_HETVE spider 6 5 0 4 9 — 0 TX5B_HETVE spider 6 5 0 4 9 — 0 TXAG_AGEOP spider 6 7 0 4 9 — 1 TXAG_AGEOR spider 6 7 0 4 9 — 0 TXC1_CUPSA spider 6 6 0 8 17 — 0 TXC1_HOLCU spider 6 6 0 4 9 — 0 TXC2_HOLCU spider 6 7 0 4 9 — 0 TXC3_HOLCU spider 6 7 0 4 9 — 0 TXC5_PHONI spider 6 4 0 4 8 — 0 TXC5_PHORI spider 6 4 0 4 10 — 0 TXC9_CUPSA spider 6 6 0 8 17 — 0 TXDP1_PARLU spider 6 7 0 4 9 — 1 TXDP2_PARLU spider 6 7 0 4 9 — 1 TXDP3_PARLU spider 6 7 0 4 9 — 0 TXDP4_PARLU spider 6 7 0 4 9 — 0 TXDT1_HADVE spider 6 5 0 4 10 — 1 TXFK1_PSACA spider 6 8 0 4 4 — 1 TXFK2_PSACA spider 6 8 0 2 4 — 0 TXFU5_OLIOR spider 6 6 0 4 10 — 0 TXG1D_PLEGU spider 6 6 0 4 6 — 0 TXG1E_PLEGU spider 6 6 0 4 6 — 0 TXG2_PLEGU spider 6 5 0 4 6 — 0 TXH10_ORNHU spider 6 8 0 2 2 — 1 TXH1_ORNHU spider 6 6 0 4 6 — 1 TXH3_ORNHU spider 6 4 0 4 6 — 0 TXH4_ORNHU spider 6 6 0 6 6 — 1 TXH5_ORNHU spider 6 5 0 4 6 — 0 TXH9_ORNHU spider 6 5 0 4 10 — 0 TXHA1_SELHA spider 6 6 0 4 6 — 1 TXHA3_SELHA spider 6 6 0 4 6 — 1 TXHA4_SELHA spider 6 6 0 6 6 — 3 TXHA5_SELHA spider 6 6 0 6 6 — 0 TXHN1_GRARG spider 6 5 0 4 6 — 1 TXHN2_GRARG spider 6 5 0 4 6 — 0 TXHP1_HETVE spider 6 6 0 4 4 — 0 TXHP2_HETVE spider 6 5 0 4 3 — 1 TXHP3_HETVE spider 6 5 0 4 3 — 0 TXJ11_DIGCA spider 7 4 0 13 13 — 0 TXI92_DIGCA spider 6 4 0 13 13 — 0 TXI1_HETVE spider 6 5 0 4 3 — 0 TXL1_ORNHU spider 4 5 0 4 6 — 1 TXLT4_LASPA spider 6 6 0 4 14 — 0 TXM10_MACGS spider 6 6 0 4 10 — 0 TXM11_MACGS spider 6 5 0 4 3 — 0 TXM31_OLIOR spider 6 6 0 4 1 — 0 TXMG1_AGEAP spider 6 6 0 4 9 — 1 TXMG1_MACGS spider 6 5 0 4 13 — 0 TXMG2_AGEAP spider 6 7 0 4 9 — 0 TXMG2_MACGS spider 6 5 0 6 13 — 0 TXMG3_AGEAP spider 6 7 0 4 9 — 0 TXMG4_AGEAP spider 6 7 0 4 9 — 0 TXMG5_AGEAP spider 6 7 0 4 9 — 0 TXMG5_MACOS spider 6 5 0 4 4 — 1 TXMG6_AGEAP spider 6 7 0 4 9 — 0 TXMG6_MACGS spider 4 9 0 4 9 — 0 TXMG7_MACGS spider 6 5 0 4 10 — 0 TXMG8_MACGS spider 6 5 0 4 7 — 0 TXMG9_MACGS spider 6 4 0 4 10 — 0 TXP1_PARSR spider 6 5 0 4 3 — 1 TXP1_PSACA spider 6 6 0 4 9 — 1 TXP2_PARSR spider 6 5 0 4 3 — 0 TXP3_APTSC spider 6 5 0 3 15 — 0 TXP3_BRASM spider 6 5 0 4 6 — 0 TXP7_APTSC spider 6 6 0 4 4 — 1 TXPR1_THRPR spider 6 5 0 4 6 — 0 TXPR2_THRPR spider 6 5 0 4 3 — 0 TXPT6_MACGS spider 6 5 0 4 13 — 0 TXR3_MACRV spider 6 5 0 4 4 — 0 TXU2_HETVE spider 6 5 0 4 3 — 0 TXVL2_CORVA spider 6 5 0 4 6 — 0 VSTX1_GRARO spider 6 5 0 4 6 — 0 VSTX2_GRARO spider 6 5 0 4 3 — 0 VSTX3_GRARO spider 6 6 0 4 6 — 0 WGRTX_GRARO spider 6 5 0 4 8 — 1 ASTAE_ASTEM spider 6 7 0 6 9 — 0 AX6A_TERSU spider 3 5 0 4 10 — 0 A2Q0G4_9VIRU virus1 6 8 0 16 7 — 0 A2Q0I8_9VIRU virus1 6 8 0 16 7 — 0 A2Q0M1_9VIRU virus1 6 6 0 16 7 — 0 A2Q0M3_9VIRU virus1 6 6 0 16 7 — 0 A2Q0M4_9VIRU virus1 8 8 0 16 7 — 0 O11874_CSV virus1 6 8 0 16 7 — 0 Q5ZNS9_9VIRU virus1 6 6 0 16 7 — 0 Q5ZNZ4_9VIRU virus1 6 6 0 17 7 — 0 Q66216_CSV virus1 6 6 0 5 7 — 0 Q66236_CSV virus1 6 6 0 5 7 — 0 Q80KH5_CSV virus1 6 6 0 14 7 — 0 Q80KH6_CSV virus1 6 6 0 14 7 — 0 Q80KH7_CSV virus1 6 8 0 17 7 — 0 Q80KH8_CSV virus1 6 8 0 16 7 — 0 Q80KH9_CSV virus1 6 6 0 16 7 — 0 Q80PW5_CSV virus1 6 6 0 16 7 — 0 Q80873_9VIRU virus1 6 6 0 16 7 — 0 Q89632_CSV virus1 6 6 0 16 7 — 0 Q91H14_9VIRU virus1 6 6 0 17 7 — 0 Q98825_CSV virus1 6 6 0 16 7 — 0 A0HYV0_9ABAC virus2 8 5 0 3 6 — 0 A8C6C4_NPVAP virus2 6 5 0 3 6 — 0 A9YMX2_9BBAC virus2 6 5 0 3 6 — 0 B0FDX4_9ABAC virus2 6 5 0 3 6 — 0 CXOL2_NPVOP virus2 6 5 0 3 6 — 0 CXOL_NPVAC virus2 6 5 0 3 6 — 0 Q06KN7_NPVAG virus2 6 5 0 3 6 — 0 Q0GYM0_9ABAC virus2 6 5 0 3 6 — 0 Q5Y4P1_NPVAP virus2 6 5 0 3 6 — 0 Q8JM47_9ABAC virus2 6 5 0 3 6 — 0 Q8QLC7_9ABAC virus2 6 5 0 3 6 — 0 Q9PYR8_GVXN virus2 6 5 0 3 6 — 0 Hypo_A cybase_cyclotide 3 4 7 1 4 5 0 circulin_F cybase_cyclotide 3 4 6 1 4 5 0 cycloviolecin_B16 cybase_cyclotide 3 4 7 1 4 5 0 cycloviolecin_B3 cybase_cyclotide 3 4 6 1 4 5 0 cycloviolecin_B4 cybase_cyclotide 3 4 7 1 4 5 0 cycloviolecin_H4 cybase_cyclotide 3 4 7 1 4 5 0 cycloviolecin_O1 cybase_cyclotide 3 4 7 1 4 5 0 cycloviolecin_O18 cybase_cyclotide 3 4 7 1 4 5 0 cycloviolecin_O7 cybase_cyclotide 3 4 7 1 4 5 0 cycloviolecin_Y5 cybase_cyclotide 3 4 7 1 4 5 0 kalata_B16 cybase_cyclotide 3 4 7 1 4 5 0 kalata_B17 cybase_cyclotide 3 4 7 1 4 5 0 mram_3 cybase_cyclotide 3 4 6 1 4 5 0 vhri cybase_cyclotide 3 4 7 1 4 5 0 vibi_E cybase_cyclotide 3 4 7 1 4 5 0 violein_A cybase_cyclotide 3 4 4 1 4 5 0 HYfl_A cybase_cyclotide 3 4 7 1 4 8 0 HYfl_F cybase_cyclotide 3 4 4 1 4 8 0 HYfl_I cybase_cyclotide 3 4 6 1 4 6 0 HYfl_J cybase_cyclotide 3 4 4 1 4 6 0 HYfl_K cybase_cyclotide 3 4 6 1 4 6 0 HYfl_L cybase_cyclotide 3 4 6 1 4 6 0 circulin_A cybase_cyclotide 3 4 6 1 4 6 0 circulin_C cybase_cyclotide 3 4 6 1 4 8 0 circulin_D cybase_cyclotide 3 4 6 1 4 8 0 circulin_E cybase_cyclotide 3 4 6 1 4 8 0 cyclopsychotride_A cybase_cyclotide 3 4 7 1 4 6 0 cycloviolein_B1 cybase_cyclotide 3 4 6 1 4 5 0 cycloviolein_B10 cybase_cyclotide 3 4 6 1 4 6 0 cycloviolein_B11 cybase_cyclotide 3 4 6 1 4 6 0 cycloviolein_B13 cybase_cyclotide 3 4 6 1 4 6 0 cycloviolein_B14 cybase_cyclotide 3 4 6 1 4 6 0 cycloviolein_B15 cybase_cyclotide 3 4 6 1 4 8 0 cycloviolein_B2 cybase_cyclotide 3 4 6 1 4 8 0 cycloviolein_B5 cybase_cyclotide 3 4 4 1 4 8 0 cycloviolein_B8 cybase_cyclotide 3 4 6 1 4 6 0 cycloviolein_B9 cybase_cyclotide 3 4 6 1 4 6 0 cycloviolein_H1 cybase_cyclotide 3 4 6 1 4 6 0 cycloviolein_O10 cybase_cyclotide 3 4 6 1 4 6 0 cycloviolein_O13 cybase_cyclotide 3 4 6 1 4 6 0 cycloviolein_O17 cybase_cyclotide 3 4 6 1 4 6 0 cycloviolein_O2 cybase_cyclotide 3 4 6 1 4 6 0 cycloviolein_O20 cybase_cyclotide 3 4 6 1 4 6 0 cycloviolein_025 cybase_cyclotide 3 4 7 1 4 6 0 cycloviolein_O3 cybase_cyclotide 3 4 6 1 4 6 0 cycloviolein_O9 cybase_cyclotide 3 4 6 1 4 6 0 cycloviolein_O5 cybase_cyclotide 3 4 6 1 4 8 0 cycloviolein_O9 cybase_cyclotide 3 4 6 1 4 8 0 cycloviolein_Y4 cybase_cyclotide 3 4 6 1 4 6 0 cycloviolein_B cybase_cyclotide 3 4 4 1 4 6 0 cycloviolein_C cybase_cyclotide 3 4 6 1 4 6 0 cycloviolein_D cybase_cyclotide 3 4 6 1 4 6 0 hcf-1 cybase_cyclotide 3 4 6 1 4 6 0 htf-1 cybase_cyclotide 3 4 6 1 4 6 0 kalata_B12 cybase_cyclotide 3 4 4 1 4 8 0 kalata_B18 cybase_cyclotide 3 4 6 1 4 8 0 kalata_B5 cybase_cyclotide 3 4 6 1 4 6 0 mram_2 cybase_cyclotide 3 4 6 1 4 6 0 mram_8 cybase_cyclotide 3 4 6 1 4 6 0 mram_9 cybase_cyclotide 3 4 6 1 4 6 1 vhi-1 cybase_cyclotide 3 5 6 1 4 6 0 vibi_I cybase_cyclotide 3 4 6 1 4 6 0 vibi_K cybase_cyclotide 3 4 6 1 4 8 0 vitri_A cybase_cyclotide 3 4 6 1 4 8 0 Hyfl_D cybase_cyclotide 3 4 6 1 4 7 0 Hyfl_E cybase_cyclotide 3 4 6 1 4 7 0 Hyfl_M cybase_cyclotide 3 4 4 1 4 7 0 PS-1 cybase_cyclotide 3 5 4 1 4 7 0 circulin B cybase_cyclotide 3 4 6 1 4 7 0 cycloviolecin_B12 cybase_cyclotide 3 4 6 1 4 7 0 cycloviolecin_B17 cybase_cyclotide 3 4 4 1 4 7 0 cycloviolecin_B6 cybase_cyclotide 3 4 4 1 4 7 0 cycloviolecin_B7 cybase_cyclotide 3 4 4 1 4 7 0 cycloviolecin_H2 cybase_cyclotide 3 4 4 1 4 7 0 cycloviolecin_H3 cybase_cyclotide 3 4 4 1 5 7 0 cycloviolecin_O11 cybase_cyclotide 3 4 6 1 4 7 0 cycloviolecin_O12 cybase_cyclotide 3 4 4 1 4 7 0 cycloviolecin_O15 cybase_cyclotide 3 4 4 1 4 7 0 cycloviolecin_O16 cybase_cyclotide 3 4 4 1 4 7 0 cycloviolecin_O19 cybase_cyclotide 3 4 6 1 4 7 0 cycloviolecin_O21 cybase_cyclotide 3 4 4 1 4 7 0 cycloviolecin_O22 cybase_cyclotide 3 4 4 1 4 7 0 cycloviolecin_O23 cybase_cyclotide 3 4 4 1 6 7 0 cycloviolecin_O24 cybase_cyclotide 3 4 4 1 5 7 0 cycloviolecin_O6 cybase_cyclotide 3 4 6 1 4 7 0 cycloviolecin_O8 cybase_cyclotide 3 4 6 1 4 7 0 cycloviolin_A cybase_cyclotide 3 4 6 1 4 7 0 kalata_B1 cybase_cyclotide 3 4 4 1 4 7 0 kalata_B10 cybase_cyclotide 3 4 4 1 5 7 0 kalata_B10_linear cybase_cyclotide 3 4 4 1 5 7 0 kalata_B11 cybase_cyclotide 3 4 4 1 4 7 0 kalata_B13 cybase_cyclotide 3 4 4 1 5 7 0 kalata_B14 cybase_cyclotide 3 4 4 1 5 7 0 kalata_B15 cybase_cyclotide 3 4 4 1 4 7 0 kalata_B2 cybase_cyclotide 3 4 4 1 4 7 0 kalata_B3 cybase_cyclotide 3 4 4 1 5 7 0 kalata_B4 cybase_cyclotide 3 4 4 1 4 7 0 kalata_B6 cybase_cyclotide 3 4 4 1 5 7 0 kalata_B7 cybase_cyclotide 3 4 4 1 4 7 0 kalata_9 cybase_cyclotide 3 4 4 1 4 7 0 mram_1 cybase_cyclotide 3 4 6 1 4 7 0 mram_10 cybase_cyclotide 3 4 6 1 4 7 0 mram_11 cybase_cyclotide 3 4 4 1 4 7 0 mram_13 cybase_cyclotide 3 4 4 1 4 7 0 mram_14 cybase_cyclotide 3 4 6 1 4 7 0 mram_4 cybase_cyclotide 3 4 6 1 4 7 0 mram_5 cybase_cyclotide 3 4 6 1 4 7 0 mram_6 cybase_cyclotide 3 4 6 1 4 7 0 mram_7 cybase_cyclotide 3 4 6 1 4 7 0 varv_peptide_A cybase_cyclotide 3 4 4 1 4 7 0 varv_peptide_B cybase_cyclotide 3 4 4 1 4 7 0 varv_peptide_C cybase_cyclotide 3 4 4 1 4 7 0 varv_peptide_D cybase_cyclotide 3 4 4 1 4 7 0 varv_peptide_E cybase_cyclotide 3 4 4 1 4 7 0 varv_peptide_F cybase_cyclotide 3 4 4 1 4 7 0 varv_peptide_G cybase_cyclotide 3 4 4 1 5 7 0 varv_peptide_H cybase_cyclotide 3 4 4 1 5 7 0 vhi-2 cybase_cyclotide 3 4 4 1 5 7 0 vibi_A cybase_cyclotide 3 4 4 1 4 7 0 vibi_B cybase_cyclotide 3 4 4 1 4 7 0 vibi_C cybase_cyclotide 3 4 4 1 4 7 0 vibi_D cybase_cyclotide 3 4 4 1 4 7 0 vibi_F cybase_cyclotide 3 4 6 1 4 7 0 vibi_G cybase_cyclotide 3 4 6 1 4 7 0 vibi_H cybase_cyclotide 3 4 6 1 4 7 0 vibi_I cybase_cyclotide 3 4 6 1 4 7 0 vico_A cybase_cyclotide 3 4 6 1 4 7 0 vico_B cybase_cyclotide 3 4 6 1 4 7 0 viciapeptide_1 cybase_cyclotide 3 4 4 1 4 7 0 vodo_M cybase_cyclotide 3 4 4 1 4 7 0 vodo_N cybase_cyclotide 3 4 4 1 4 7 0 CD-1 cybase_cyclotide 3 4 6 1 6 8 0 Hyfl_B cybase_cyclotide 3 4 6 1 4 8 0 Hyfl_C cybase_cyclotide 3 4 6 1 4 8 0 cycloviolecin_O14 cybase_cyclotide 3 4 4 1 5 8 0 kalata_B8 cybase_cyclotide 3 4 4 1 5 8 0 kalata_B9 cybase_cyclotide 3 4 4 1 5 8 0 kalata_B9_linear cybase_cyclotide 3 4 4 1 5 8 0 mram_12 cybase_cyclotide 3 4 4 1 4 8 0 palicourein cybase_cyclotide 3 4 4 1 4 8 1 cycloviolecin_Y1 cybase_cyclotide 3 4 4 1 5 10 0 cycloviolecin_Y2 cybase_cyclotide 3 4 4 1 5 10 0 cycloviolecin_Y3 cybase_cyclotide 3 4 4 1 5 10 0 tricyclo_A cybase_cyclotide 3 4 4 1 5 10 0 tricyclo_B cybase_cyclotide 3 4 4 1 5 10 0 Loop Sequences Database identifier Loop 1 Loop 2 Loop 3 Loop 4 Loop 5 Loop 6 TACA1_TACTR QLQGFN VVRSYGLPTIP RGLT RSYFPGSTYGR TACA2_TACTR QLQGFN VVRSYGLPTIP RGLT RSYFPGSTYGR TACB1_TACTR LFRGAR RVYSGRS FGYY RRDFPGSIFGT TACB2_TACTR LFRGAR RVYSGRS FGYY RRDFPGSIFGT A0ZSG4_FUGRU LPLGGS KSPGTE DFCAF QCRLFRTVCY A0ZSG5_FUGRU SQLTQS VPQFG HPQAL HCRFFNAICF A0ZSG6_FUGRU IPHQQS LGYPLP DPCDT YCRFFNAICY A0ZSG7_FUGRU SRLMES SPYTP DPCAS HCRLFNTICN A1YL76_9PRIM VATRGS KPPAPA HPCAS QCRFFRSACS A2ALT3_MOUSE VATRDS KPPAPA DPCAS QCRFFGSACT A4GVF2_CANLU VATRNS KSPAPA DPCAS QCRFFRSACT A5JUA3_9GALL VRLLES LGHQIP DPCAT YCRFFNAFCY A5JUA4_TRATE VRLLES LGHQIP DPCAT YCRFFNAFCY A5JUA5_TRASA VRLLES LGHQIP DPCAT YCRFFNAFCY A5JUA6_SYRRE VRLLES LGHQIP DPCAT YCRFFNAFCY A5JUA7_ROLRO VRLLES LGHQIP DPCAT YCRFFNAFCY A5JUA8_PERPE VRLLES LGHQIP DPCAT YCRFFNAFCY A5JUA9_POLMA VRLLES LGHQIP DPCAT YCRFFNAFCY A5JUB0_PAVMU VRLLES LGHQIP DPCAT YCRFFNAFCY A5JUB1_9GALL VRLLES LGHQIP DPCAT YCRFFNAFCY A5JUB2_POLSM VRLLES LGHQIP DPCAT YCRFFNAFCY A5JUB3_PHACC VRLLES LGHQIP DPCAT YCRFFNAFCY A5JUB4_PAVCR VRLLES LGHQIP DPCAT YCRFFNAFCY A5JUB6_MELGA VRLLES LGHQIP DPCAT YCRFFNAFCY A5JUB7_9GALL VRLLES LGHQIP DPCAT YCRFFNAFCY A5JUB9_LOPNY VRLLES LGHQIP DPCAT YCRFFNAFCY A5JUC0_LAGLG VRLLES LGHQIP DPCAT YCRFFNAFCY A5JUC1_LOPIM VRLLES LGHQIP DPCAT YCRFFNAFCY A5JUC2_LOPSD VRLLES LGHQIP DPCAT YCRFFNAFCY A5JUC3_LOPDI VRLLES LGHQIP DPCAT YCRFFNAFCY A5JUC4_GALSO VRLLES LGHQIP DPCAT YCRFFNAFCY A5JUC5_FRAPO VRLLES LGHQIP DPCAT YCRFFNAFCY A5JUC6_9GALL VRLLES LGHQIP DPCAT YCRFFNAFCY A5JUC7_CATWA VRLLES LGHQIP DPCAT YCRFFNAFCY A5JUC8_CROMA VRLLES LGHQIP DPCAT YCRFFNAFCY A5JUC9_COTIA VRLLES LGHQIP DPCAT YCRFFNAFCY A5JUD0_COTCO VRLLES LGHQIP DPCAT YCRFFNAFCY A5JUD1_CROCS VRLLES LGHQIP DPCAT YCRFFNAFCY A5JUD4_ALECH VRLLES LGHQIP DPCAT YCRFFNAFCY A5JUD5_AFRCO VRLLES LGHQIP DPCAT YCRFFNAFCY A5JUD6_ARGAR VRLLES LGHQIP DPCAT YCRFFNAFCY A5JUD7_ALERU VRLLES LGHQIP DPCAT YCRFFNAFCY A7YMS3_PERMA VATRDS KPPAPA DPCAS QCRFFRSVCS A7YMS6_PERPL VATRDS KPPAPA DPCAS QCRFFRSVCS A7YMS8_PERPL VATRDS KPPAPA DPCAS QCRFFRSVCS A9EDH6_COTIA VPNFKT KPHLNS NYCAL KCRIPQTICQ A9EDJ0_COTIA VPNFKT KPHLNS NYCAL KCRIPQTICQ A9JPS5_CAPHI VATRDS KPPAPA DPCAF QCRFFRSACS AGRP_BOVIN VRLHES LGHQVP DPCAT YCRFFNAFCY AGRP_HUMAN VRLHES LGQQVP DPCAT YCRFFNAFCY AGRP_MOUSE VRLHES LGQQVP DPCAT YCRFFNAFCY AGRP_FIG VRLHES LGHQVP DPCAT YCRFFNAFCY ASIP_BOVIN VATRDS KPPAPA DPCAF QCRFFRSACS ASIP_CALGE VSTRGS KPPAPA HPCAS QCRFFRSACS ASIP_CALGO VSTRGS KPPAPA HPCAS QCRFFRSACS ASIP_CALIA VSTRGS KPPAPA HPCAS QCRFFRSACS ASIP_CANFA VATRNS KSPAPA DPCAS QCRFFRSACT ASIP_CEBPY VSTRGS KPPAPA HPCAS QCRFFRSACS ASIP_CERAE VATRDS KPPAPA DPCAS QCRFFRSACS ASIP_CERMI VATRDS KPPAPA DPCAS QCRFFRSACS ASIP_COLPO VATRDS KPPAPA DPCAS QCRFFRSACS ASIP_ERYPA VATRDS KPPAPA DPCAS QCRFFRSACS ASIP_FHLCA VATRDS KPPAPA DPCAS QCRFFRSACS ASIP_GORGO VATRNS KPPAPA DPCAS QCRFFRSACS ASIP_HORSE VATRDS KPPAPA DPCAS QCRFFRSACS ASIP_HUMAN VATRNS KPPAPA DPCAS QCRFFRSACS ASIP_LEOCY VATRGS KPPAPA HPCAS QCRFFRSACS ASIP_LEORO VATRDS KPPAPA HPCAS QCRFFRSACS ASIP_MACAR VATRDS KPPAPA DPCAS QCRFFRSACS ASIP_MACAS VATRDS KPPAPA DPCAS QCRFFRSACS ASIP_MACCY VATRDS KPPAPA DPCAS QCRFFRSACS ASIP_MACFA VATRDS KPPAPA DPCAS QCRFFRSACS ASIP_MACFU VATRDS KPPAPA DPCAS QCRFFRSACS ASIP_MACHE VATRDS KPPAPA DPCAF QCRFFRSACS ASIP_MACMR VATRDS KPPAPA DPCAS QCRFFRSACS ASIP_MACMU VATRDS KPPAPA DPCAS QCRFFRSACS ASIP_MACNE VATRDS KPPAPA DPCAS QCRFFRSACS ASIP_MACNG VATRDS KSPAPA DPCAS QCRFFRSACS ASIP_MACNR VATRDS KPPAPA DPCAS QCRFFRSACS ASIP_MACRA VATRDS KPPAPA DPCAS QCRFFRSACS ASIP_MACSI VATRDS KPPAPA DPCAS QCRFFRSACS ASIP_MACSL VATRDS KPPAPA DPCAS QCRFFRSACS ASIP_MACSY VATRDS KPPAPA DPCAS QCRFFRSACS ASIP_MOUSE VATRDS KPPAPA DPCAS QCRFFGSACT ASIP_PANPA VATRNS KPPAPA DPCAS QCRFFRSACS ASIP_PANTR VATRNS KPPAPA DPCAS QCRFFRSACS ASIP_PAPAN VATRDS KPPAPA DPCAS QCRFFRSACS ASIP_PIG VANRDS KPPALA DPCAF QCRFFRSACS ASIP_PONPY VATRNS KPPAPA DPCAS QCRFFRSACS ASIP_RAT VATRDS KPPAPA NPCAS QCRFFGSACT ASIP_SEMEN VATRYS KPPAPA DPCAS QCRFFRSACS ASIP_TRAAU VATRDS KPPAPA DPCAS QCRFFRSACS ASIP_TRACR VATRDS KPPAPA DPCAS QCRFFRSACS ASIP_TRAFR VATRDS KPPAPA DPCAS QCRFFRSACS ASIP_TRAOB VATRDS KPPAPA DPCAS QCRFFRSACS ASIP_VULVU VATRNS KSPAPA DPCAS QCRFFRSACT B0B577_RABIT VATRDS KPPAPV DPCAS QCRFFRSVCT B0ZDU0_COTIA VPNFKT KPHLNS NYCAL KCRIFQTICQ B0ZDU2_CHICK VPNFKT KPHLNS NYCAL KCRIFQTICQ B0ZDU3_CHICK VPNFKT KPHLNS NYCAL KCRIFQTICQ B0ZDU4_CHICK VPNFKT KPHLNS NYCAL KCRIFQTICQ Q3UU47_MOUSE VRLHES LGQQVP DPCAT YCRFFNAFCY Q4JNX9_CAPHI VATRDS KPPAPA DPCAF QCRFFRSACS Q4SEW0_TETNG IPHQQS LGYPLP DPCDT YCRFFNAICY Q4SP72_TETNG SRLKDS SPYMF DPCAS HCRLFNTICN Q5CC33_CARAU VPLWGS KTPSAA DQCAF HCRLFKTVCY Q5CC34_CARAU VPLWGS KTPSAA DQCAF HCRLFKTVCY Q5CC35_CARAU VPLWGS KTPSAA DQCAF HCRLFKTVCY Q5IRA5_CANFA VATRNS KSPAPA DPCAS QCRFFRSACT Q6SGX9_CANLU VATRNS KSPAPA DPCAS QCRFFRSACT Q6SGY0_CANLA VATRNS KSPAPA DPCAS QCRFFRSACT Q6J648_SHEEP VRLHES LGHQVP DPCAT YCRFFNAFCY Q70Q61_CARAU IPHQQS LGHHLP NPCDT YCRFFKAFCY Q70Q62_CARAU IPHQQS LGHHLP NPCDT YCRFFKAFCY Q90WY7_COTJA VRLLES LGHQIP DPCAT YCRFFNAFCY Q9GLM5_PIG VRLHES LGHQVP DPCAT YCRFFNAFCY Q9PWG2_CHICK VRLLES LGHQIP DPCAT YCRFFNAFCY Q9QXJ3_RAT VRLHES LGQQVP DLCAT YCRFFKTCY Q9W7R0_CHICK VRLLES LGHQIP DPCAT YCRFFNAFCY IAAI_AMAHP IPKWNR GPKMDGVP HPYT TSDYYGN ADO1_AGRDO LPRGSK LGENKQ KGTT MFYANR IOB1_ISYOB LPRGSK LGENKQ EKTT MFYANR PIU1_PETTU IAPGAP FGIDKP NPRAW SSYANK A11GB QRANFV DAFHHAAV EGV YLV ABVIA SPPGSY FGPAA SNF STLSDV ABVIB TPPGGA GGHAH SQS DULAST ABVIC TPPGGA GGHAH SQS NULAST ABVID TPRHGV FYSYF SKA NPSSKR ABVIE TPPEVG LFAYE SKI WRPR ABVIF TPPGGY YHPDP SQV NFPRKH ABVIF cootant 1 TPPGGY YHPDP SQY NFPRKH ABVIG TAPGGA YAAYT SNA NLNTKK ABVIG mutant 1 TAPGGA YADNT SNA NLNTKK ABVIH TPAGDA DATTK IPF NLATKK ABVII TPAGDA DATTE ILF NLATKK ABVIJ TPAGDA DATTE ILF NLATKE ABVIK TPAGGA DATTE ILF NLATKK ABVIL TPGGEA DATTN FLT NLATNK ABVIM LGSGEL VRDTS SMS TNNI ABVIN LGSREQ VRDTS SMS TNNI ABVIO LGSREL VRDTS SMS TNNI AVIA SNAGAF GIHPGL SFJ IVW Ai6.1 KQSGEM NLLDQN EGY IVLV Ai6.2 TQSGEL DVIDPD NNF IIFF Ai6.3 YDGGTS NTGNQ SGW IFI Am2766 KQAGES DIFSQN VGT AFI Ar6.1 LEKGVL DPSAGN SGE VLV Ar6.10 ADLGEE YTRF PGLR KDLQVPT Ar6.11 GEQGEG ATRP AGLS VGSRPGGL Ar6.12 GNLGES SAHR PGLM MGEASI Ar6.13 SNFGSD IPATHD SGE FGFEDMGL Ar6.14 TPVGGY SRHHI1 SNH IKSIGR Ar6.15 TPVGGY FDHHH SNH IKSIGR Ar6.16 TPVGGY SRHYH SNH IKSIGR Ar6.17 TPVGGS SRHYH SLY NKNIGQ Ar6.18 SPNGGS SRHYH SLW NK Ar6.19 TVDSDF DPDNHD SGR IDEGGSGV Ar6.2 VDGGTF GFPKIGGP SGW IFV Ar6.20 HES EEEEKT GEXDGEPV ARF Ar6.21 HEY EDEEKT GLEDGEPV ATT Ar6.22 HEY EEEEKT GEEDGEPV AEF Ar6.24 HEY EDEEKT GEEDGEPV ARF Ar6.25 EES EEEEKH EENNGVYT LRY Ar6.26 EEN EEEEKH NTNNGPS APQ Ar6.27 EES EDEEKH NTNNGPS APQ Ar6.28 EES EEEEKT GLENGQFF SRI Ar6.3 RALGEY GLPYVHNSR SQL GFI Ar6.4 LPPLSL TMADDE HD ILFL Ar6.5 LPPLSL TMDDDE DD ILFL Ar6.6 LPPLSL TMDDDE DD XLFL Ar6.7 LPPLHW NMVDDE EF VLLA Ar6.8 LPPLSL NMADDD ND VLFL Ar6.9 ADLGEE HTRF PGLR EDLQVPT AsVIIA XQKGEG SLDVE SSS KPGGPLFDFD Ar6.1 TPPGTY VGPST SDV SMSNV Ar6.2 TPPSGY YHPYY SRA NLTRKR Ar6.3 THAYEA DATTN YMT NLPTRK Ar6.4 TSPDGA NTPPQ SKY ISISTT Ar6.5 THPGGA AGHHH SQS NTAANS Ar6.6 TFPGGA YYHSQ GDF QRYINS Ar6.7 TFPEGA NHPEH EDF DRGRNR Ar6.8 TPPEDY TYHRD DLY NKITNV Ar6.1 XAENEI WIFIQN DGT LLI Ar6.2 LELGEL NFFFPT GY VLLV Ar6.3 EPPGNF GMIKIGPP SGW FFA BVIA SAPGAF LIRPGL SEF FFA BcB42 NDPGGS TRHYH QLY NKQESV BcB54 KGWSVY SWDEE SGE TRYY Bromosleeper peptide EET NVIFKT GPPGDWQ VEA C6.1 SNAGAF GIHPGL SEL LGW C6.2 KGKGAS RRTSYD TGS RSGR C6.3 KGKGAS RRTSYD TGS RSGR C6.4 KSTGAS RRTSYD TGS RSGR C6.5 QGRGAS RKTMYN SGS RSGR C6.6 QGRGAS RKTSYD TGS RSGR C6.7 KSTGAS RKTSYD TGS DRGR C6.8 QGRGAS RKTSYD TGS RSGR CVIA XSTGAS RRTSYD TGS RSGR CVIB KGKGAS RKTMYD RGS RSGR CVIC KGKGQS SKLMYD TGS SRRGK CVID KSKGAK SKLMYD SGS SGTVGR CVIE SNAGAF GIHPGL SEL LVW Co6.1 VDFGFF GPGFGD TGF LLV CaFr179 EED EDEEKH NTNNGPS ARE CaHr91 REQSQG TNTSPP SGLR SGQSQGGV Cn6.1 YNAGTF GIRPGL SEF FLW CnVIA YSTGTF GINGGL SNL LFFV CnVIIA KGKGAP TRLMYD HGS SSSKGR Co6.1 TPPGSH TGHSD SDF STMSDV Co6.2 TPRNGV FYSYF SRA NPSTKR Co6.3 TSPGGA YSAST SKA NLTTKR Co6.4 MHPEGG RFSYE SKI YTPSFT Co6.5 TFAGKA DATAT VLF NLVTNK Co6.6 TDPGGA GNPGH SKF ITTSST Co6.7 REPGDL AGDAS EHS NTVHT Conotoxin-1 DEEGTG SSDSE SGR TFEGLFEF Conotoxin-10 GGQGEG YTQP PGLR RGGGTGGGA Conotoxin-12 GGQGKG YTQP PGLR RGGGTGGGV Conotoxin-15 RPSGSP GVTEI GR SRGK Conotoxin-2 GGQGEG YTQP PGLR RGGGTGGGV Conotoxin-2.7 IADDMP GFGLFGGPL SGW LFV Conotoxin-3 ESYGKP GIYND NA DPAKKT Conotoxin-5 REGGEF GTLYEER SGW FFV Conotoxin-6 REGGEF GTLYEER SGW FFV Conotoxin-8 GGQGEG YTQP PGLR RGGGTGGGS Conotoxin-9 SSGGTF GIHPGL SEF FLW Cv conotoxin IAVGQL VFWNIGRP SGL VFA Da6.1 PREHQL DLIFQN RGWY LLRP Da6.2 SEEGQL DPLSQN RGWH VLVS Da6.3 LGGGEV DIFFPQ GY ILLF Da6.4 AQSSEL DALDSD SGV MVFF Da6.5 YDGGTG DSGNQ SGW IFV Da6.6 QEKWDY PVPFLGSRY DGM PSFF Da7 QGEWEF TVPVLGFVY PWLI GPFV Da7a IPGGEN DVFRPYR SGY ILLL DaVIIA XPKNNL AIIEMAE SGF LIYR Di6.1 LGFGFA LMLYSD SY VGAV Di6.2 YLLYHF GINGGL SNL LFFV Di6.3 NEAQEH TONPD SES NKFVGR E6.1 KPKGPK FPHQKDGLVST NKT TRSK E6.2 TPHGGS SLPILKNGL GR SVPRNK EVIA IKXYGF GIKPGL SGA VGV EVIB YPPGTF NSHDQ SEL LPAV Eb6.1 THSGGA NSHTQ NAF DTATRT Eb6.10 TRSGGA NSHTQ DDF DTATRT Eb6.11 TRSGGA NSHTQ NAF DTATRT Eb6.12 TRSGGA YHRDT DDF STATST Eb6.13 TQTNGA NSHDQ SKS NLTINR Eb6.2 AHSGGA NSHDQ NAF DTATRT Eb6.3 THSGGA NSHDQ NAF DTATRA Eb6.4 THSGGA NSHDQ NTF DTATRT Eb6.5 TRSGGA NSHDQ NAF DTATRT Eb6.6 THSGGA NSHNQ NAF DTATRT Eb6.8 THSGGA NSHTQ DDF STATST Eb6.9 TRSGGA NSHTQ DDF STATST Ep6.1 LGFGEA LMLYSD SY VALV G6.1 EPPGDF GFFKIGPP SGW FLW GVIA XSPGSS SPTSYN KS NPYTKR GVIIA XSPGTP SRGMRD TS LLYSNK GVIIB XSPGTP SRGMRD TS LSYSNK Ge6.1 LDPGYF GTPFLGAY GGI LIV Gla(1)-TxVI KDGLIT LAPSE SED EGS Gla(2)-TxVI/A SDDWQY ESPTD SWD DVV Gla(2)-TxVI/B SDDWQY ESPTD SWD DVV Gla(3)-TxVI PDYTEP SHAHE SWN YNGH Gm6.1 REGAES DVISQN QGT VFF Gm6.2 KQADES NVFSLD TGL LGF Gm6.3 VPYEGP NWLTQN DEL VFF Gm6.4 YDGGTG DSGNQ SGW IFA Gm6.5 QALWDY PVPLLSSGD YGLI GPFV GmVIA RKEGQL DPIFQN RGWN VLF Im6.1 DPYY NDGKV PEYPT GDSTGKLI I6.1 TRPGGA YYDSH RHV HEVFNT I6.2 TPPGGA NIHFH ERP DMANNR King-Kong 1 IEQFDP EMISHT VGV FLMA King-Kong 2 APFLHP TFFFPN NSY VQFI LVVICs TPRNGF RYHSD SHF HTWMM LeD51 RDGLTT LAPSE SGN EQN LiC42 GHSGAG YTRF PGLH SGGHAGGL LiC53 TAPSGY DYPEE EVE GRHY LiCr173 NEY EERDEN GKANGEPR ARM LiCr95 DPPGDS SRWYNH SKL TERNSGPT Lp6.1 VELGHI ATGFFLDEE TGS HVP Lt7b TDWLGS SSPSE YDN HTY LtVIA AYISEP DILP PGLK NEDFVPI LtVIB SSPDES TYHYN QLY NKEENV LtVIC KYAGSP GLVSE GT NVLRNR LtVID TDEGGD DPGNHN RGS LVLQHKAV LtVIE TDEGGD DPGNHN RGS LVLQHKAV LtVIIA LGWSNY TSHSI SGE ILSY Lv6.1 PNTGEL DVVEQN YTY FIVV LvVIA.1 SPAGEV TSKSP TGFL SHIGGM LvVIA.2 SPAGEV TSKSP TGFL THIGGM LvVIA.3 SPGGEV TSKSP TGFL SHIGGM LvVIB.1 SPGGEV TRHSP TGFL NHIGGM LvVIB.2 SPGGEV TRHSP TGFL NHIGGM LvVICb TPRNGF RYHSH SNF HTWATM LeVID TPRNGA GYHSH SNF HTWANY M1 TPSGGA YVAST SNA NLNSNK M12 TPRHGV FYSYF SKA NPSSKR M15 TPPGGS GGHAH SKS NTMAST M19 LGSGEQ VRDTS SMS TNNI M23 SPPGSY FGPAA SNF STMSDV M25 TPPEGG LSSYE SKI WRPR M26 TPAGDA DATTN ILF NLATKK M6.1 KQADEP DVFSLE TGI LGF M6.2 YNAGTF GIKPGL SAI LSFV MVIA YNAGTF GIRPGL SEF FLW MVIB YNAGSF GIHPGL SEF ILW MVIC YPPGTF GIKPGL SAI LSFV MVID YNAGTF GIKPGL SAI LSFV MVIIA KGKGAK SRLMYD TGS RSGK MVIIB KGKGAS HRTSYD TGS NRGK MVIIC KGKGAP RKTMYD SGS GRRGK MVIID QGRGAS RKTMYN SGS NRGR MaI51 EDVWMP TSNWE SLD EMY MaIr137 EPPGDF GFFKIGPP SGW FLW MaIr193 RPPGMV GFPKPGPY SGW FAV MaIr332 LDGGFI GILFFS SGW IVLV MaIr34 LEADYY VLPFVGNGM SGI VFV MaIr94 LESGSL FAGYGHSS SGA LDYGGLGVGA MgI42 NNRGGG SQHPH SGT NKTFGV MgIr112 DPKWTI NNDAE FPYS ENSN MgIr93 NNRGGG SQHFH SGT NKIFGV MgIr99 KGKGAG DYSHE SRQ TGRIFQT MiFr92 KHQNDS AEEGEE SDLR MTSGAGAI MiFr93 NDRGGG SQHPH GGT NKLIGV MiFr95 RSKGQG TNTAL PGLE EGQSQGGL Mik41 RSSGRY RSPYD RRY RRITDA Mik42 DAPNAP EKFDND DA MLREKQQTI Ml6.1 TPPGSD NGHSD SNV STMSYV Ml6.2 TPRNGY YYRYF SRA NLTIKR Ml6.3 TPSGGA YYDYF SMT NFNSKS Ml6.4 ADGGDL DPSSDN SE IDEGGSGV Mr6.1 LDAGEM DLFNSK SGW IILF Mr6.2 PNTGEL DVVEQN YIY FIVV Mr6.3 PNTGEL DVVEQN YIY FIVV MrVIA RKKWEY IVPIIGFIY PGLI GPFV MrVIB SKKWEY IVPILGFVY PGLI GPFV NgVIA FSPGTF GIKPGL SVR FSLF Om6.1 VPHEGP NWLTON SGYN IIFF Om6.2 LAEHET NIFTQN EGV IFI Om6.3 IPHFDP DPTRHT EGL ILIA Om6.4 LGFGEA LILYSD GY VGAI Om6.5 HPPGNF GMIKIGPP SGW FFA Om6.6 QRRWDF PGSIVGVTT GGLI FLFF P2a KTPGRK FPHQKD GRA UTT P2b KKSGRK FPHQKD GRA UTT P2c KKTGRK FPHQKD GRA UTT P6.1 YPPGTF GIKPGL SEL LPAV PVIA YAPGTF GIKPGL SEF LPGV PVIIA RIPNQK FQHLDD SRK NRFNR Pn6.1 VKYLDP DMLRHT FGL VLIA Pn6.10 EES EDEEKH HENNGVYT LRY Pn6.11 EEY EDEEKT GLEDGFPV ATT Pn6.12 FESWVA ESPKR SHV LFV Pn6.13 IAESEP NTITQN DGK LKF Pn6.14 QRRWDF PGALVGVTT GGLI LGVM Pn6.2 LGFGEV NFFFPN SY VALV Pn6.3 IPQFDP DMVRHT KGL VLIA Pn6.5 KAESEA NITTQN DGK LFF Pn6.6 FESWVA ESPKR SHV LFV Pn6.7 LEVDYF GIFFVNNGL SGN VFV Pn6.8 SDQWKS SYPHE RWS NRY Pn6.9 DDWLAA TTPSQ IEV DGF PnVIA LEVDYF GIPFANNGL SGN VFV PnVIB EPPGNF GMIKIGPP SGW FFA PnVIIA TSWFGR TVNSE SNS DQTY Pn6.1 VEDGDF GPGYEE SGF IYV PnIA RPVGQY GIPYEHNWR SQL AII PnIIA NTPTQY TLHRH SLY HKTTHA Qc6.1 AAAGEA VIFAGNVF KGY LFV Qc6.2 QDSGVV GFPKPEPII SGW LFV QcVIA PW GFT LPNY QGLT RVIA KPPGSP RVSSYN SS KSYNKK RVIIA TYWLGP EVDDT SAS RSKF S6.1 KAAGKS SRIAYN TGS RSGK S6.10 TPDDGA AEPVQ STF NPVTNM S6.11 RTWNAP SFTSQ FGK AHHR S6.2 RSSGSF GVTGI GR YRGK S6.6 KGKGAP RKTMYD SGS GRRGK S6.7 MEAGSY GSTTRI GY AYSASKNV S6.8 SNAGGF GIHPGL SFI LVW SO3 KAAGKP SRIAYN TGS RSGK SO4 IEAGNY GPTVMKI GF SPYSKI SO5 MEAGSY GSTTRI GY AYFGKK SVIA RSSGSF GVTSI GR YPGK SVIA mutant 1 RPSGSF GVTSI GR YPGK SVIB KLKGQS RKTSYD SGS GRSGK SVIE SSGGTF GIHPGL SEF FLW SmVIA SSGGTF GIRPGL SEF FLW SmVIIA LQFGST FLGDDDI SGE FYSGGTFGI St6.1 YPPGTF GIKPGL SEL LFAV St6.2 YSTGTF GINGGL SNL LFAV St6.3 MKAGSY VATIRI GY AYFGKI TVIA LSPGSS SPTSYN RS NTYSRK TVIIA SGRDSE FPV MGLM SRGK TeA53 MLWFGR TKDSE SNS DKTY Textile convaissed PY YVY PPAY EASG peptide Ts6.1 WPQVWF GLQRG PGTT FFL Ts6.2 SGWSVY TSDPE SGE SSYY Ts6.3 TPWLGG TSPEE PGN ETY Ts6.4 NEY DDRNKE GRTNGHPR ANV Ts6.5 NEH EDRNKE GRTNGHPR ANV Ts6.6 NEY DDRNKE GRTNGHPR ANV Ts6.7 DEY EDLNKN GLSNGEPV ATA Tx6.1 RKEHQL DLIFQN RGWY VVLS Tx6.2 APFLHL TFFFPN NGY VQFI Tx6.3 YDSGTS NTGNQ SGW IFVS Tx6.4 EPPGNF GMIKIGPP SGW FFA TxIA/TxVIA KQSGEM NILDQN DGY IVLV TxIB/TxVIB KQSGEM NVLDQN DGY IVFV TXMEKL-011 KDGLTT LAPSE SGN EQN TxMEKL- TSWLAT TDASQ TGV YKRAY 022/tXMEKL-021 MAWFGL SKDSE TxMEKL- SNS DVTR 0511/TxMEKL-0522 GTWFST TKDSE TxMEKL-033 SNS DQTY precarsor RGYDAP SSGAP TxMEKL-P2 KQSGEM NLLDQN DWWT SARTNR TxMKLT1-0111 LDAGEI DFFFPT DGY IVFV TxMKLT1-0141 IEQFDP DMIRHT GY ILLF TxMKLT1-015 YDGGTS DSGIQ VGV ILMA TxMKLT1-0211 QEKWDF PAPFFGSRY SGW IFV TxMKLT1-032 LDAGEV DIFFPT FGLF TLFF TxO1 YDSGTS NTGNQ GY ILLF TxO2 YDGGTS DSGIQ SGW IFV TxO3 HPPGNF GMIKTGPP SGW IFV TxO4 VPYEGP NWLTQN SGW FFA TxO5 QEXWDY PVPFLGSRY DAT VVFW TxO6 KQADEP DVFSLD DGLF TLFF TxVII GGYSTY EVDSE TGI LGV TxVIIA YGFGEA LVLYTD SDN VRSY Vc6.3 EPPGNF GMIKVGPP GY VLAV Vc6.4 YDGGTG DSGNQ SGW FFA Vc6.6 LSGGEV DFLFPK SGW IFV VcVIA HEEGQL DPFLQN NY ILLF VcVIB IPFLEP TFFFID LGWN VFV VcVIC RLWSNG RKHKE NSI AQFI VeG52 RRRGQG TQSTP SNH KGIY ViKr33 LDPGYF GTPFLGAY DGLR DGQRQGGM ViKr92 SGWSVY TQHSE GGI LIV Vn6.1 RPGGMI GFPKPGPY SGE TGNY Vn6.10 HAGGRF GFPKIGEP SGW FVV Vn6.11 IEDEKY GILPFANSGV SGW FFV Vn6.12 RQPGEF FTVVAK SYL IFV Vn6.13 LASGET WRDTS GGT LVI Vn6.14 LGSGET WLDSS SFS TNNV Vn6.15 SGSGYG KNTF SGS TNNV Vn6.16 SGSGYG KNTF AGLT RGPRQGPI Vn6.17 STAG KNTF DGLT RGPHQGPI Vn6.18 HEY EDRDKKT EGLV TGPSQFPV Vn6.19 SGESVH TQHSD GLENFEPF ATL Vn6.2 KEY EDRDKT SGE TGSY Vn6.20 YEY KEQNKT GLENGQPD ANL Vn6.21 EEY KEQNKT GISNGPT VGG Vn6.22 RGWSNG TTNSD GLTNGRPR VGV Vn6.3 TGWLDG TSTAE SNN DGTF Vn6.4 RTWYAF NFPSQ TAV DAT Vn6.5 VGLSSY GPWNNPP SEV SSKTGR Vn6.6 VGWSSY GPWNNPP SWYT DYY Vn6.7 VAGGHF GFPKIGGP SWYT DYY Vn6.8 AAGGQF GFPKIGGP SGW FFV Vn6.9 NNRGGG SQHPH SGW LGV VxVIA TDDSQF DPNDHD SGT NKTFGV VxVIB SGRGSR FPQ SGE IDEGGRGV conocoxin-GS SRRGHR IRDSQ MGLR GRGNPQK ArXL4 SWPGQE EHDSD GGM CQGNR Au11.6 RAEGTY ENDSQ GSF CVGRR BeTX LSLGQR ERHSN LNE CWGG Bt11.1 LSLGQR GRHSN GYL CFYDK Bt11.4 FPPGVY TRHLP GYL CFYDK Cp1.1 FPPGIY TPYLP RGK CSGW Em11.10 SGIGQG GQDSN WGI CGT Ep11.1 LSEGSP SMSGS GDM CYGOQ Ep11.12 HHEGLP TSGDG HKS CRST Fi11.11 GKDGRA DYHAD GME CGGV Fi11.1a KKDRKP SYHAD N CLGGI Fi11.6 KADEEP EYHAD N CLSGI Fi11.8 LRDGQS GYDSD N CWGY Im11.1 RLEGSS RRSYQ RYS CIRF Im11.2 TSEGYS SSDSN HKS CWNV Im11.3 SGSGEG DYESE KNV CIESM L11.5 GKDGRQ RNHAD GER CPIGT M11.1a SNKGQQ GDDSD N CYNNK M11.2 GKDGRK GYHAD WHL CLSGI M11.5 FPPGTF SRYLP N CSGW Mi11.1 GKDGRK GYHAD SGR CLSGI R11.1 GKDGRK GYHAD N CLSGI R11.10 GRDGRA DYHAD N CLGGI R11.11 GKDRRK GYHAD N CLSGI R11.12 GKDGRK GYHAD N CLSGI R11.13 GKDGRK GYHAD N CLSGI R11.15 GKDGRR GYHAD N CLSGI R11.16 KANGKP SYHAD N CLSGI R11.17 GKDGRQ RNHAD N CLSGI R11.18 GKDGRQ RNHAD N CPFGT R11.2 WVGRVH TYHAD N CPIGT R11.3 GRDGRQ RNHAD PSV CFKGR R11.5 KADEKP EYHSD N CPIGT R11.7 KADEKP EYHAD N CLSGI RXIA RANGKP SYHAD N CLSGI RXIB RADEKP KYHAD N CLSGI RXIC KKDRKP SYHAD N CLGGI RXID KINKMS SLHEE N CLSGI RXIE QAYGSS SAVVR RFR CFHGK RgXIA KRDRKP SYQAD DPNAV CQYFSDAV S11.2a VPPSRY TRHRP N CPIGT S11.3 RTEGMS EFNQQ RGT CSGL SrXIA RAEGIY ENDSQ WRS CRGE Sx11.2 IPEGSS SSSGS LNE CWGG TxXI FPPGIY TPYLP EKS CRWT ViTx FPPGIY TPYLP WGI CGT Vx11.1 FPPGIY TPYLP WGI CDT Vx11.2 NSS TRAFD WGI CDT AVR9_CLAFU GQL FNNKD LGQ GR DFHKLQ U499_ASPCL GQV TGKND GGP PK NTKEGV U499_ASPTN GQV LNKTG SGF NK VNFV U499_NEOFI IAKGEV HQTGET GGK PK DMRSLT A6RPC6_BOIFB LPQGES MMQHDK DGFK ALAEGGKADVGF A6SKI6_BOTFB IKNGEV HLTGES EGLM NSGE A7SBW4_SCLS1 LGRDHD DPDGREL DGFK ALAHGGKANVGY B0CWT3_LACBS VIKGKI SRDSD RGLI APFGPFGGS B0DIS7_LACBS FIALTP AADKD KEV FPVPFGNGGV B0DQK7_LACBS LMDGSY MSNSD SGL KISLSAVGLGLR B0DQL1_LACBS YVRGDY QIDSD SEL VVFESSPLSRTVFVDW B0DQL3_LACBS FGLGSP SFNSN GRI YPFAPEMVYGF B0DUS4_LACBS FALGTL SFDSN SGY LIIPPTTVLGF B0DVV7_LACBS HSILTS RVDTD SGH NSIPLIFVLGF U499_CHAGB RAILTT RVTSD AGLK GIFDEDAL U499_NSUCR RRHSLYVDFSDVGWNDWI QGE SGMK VSADGESV A0MK33 VAPPGYHAFY PFPLADHLNSTNHAIVQTL VPTDLSPVSLLYLDEYERV G VNSVNTNIPKAC ILKNYQDMVVFG A0MK34 RRHPLYVDFSDVGWNEWI NGE PFPLSDHLNSTNHAIVQTL VPTELSPISLLYLDEYEKV G VAPPGYHAFY VNSVNSNIPRAC VLRNYQDMVVEG A0MK35 RRHALYVDFSDVGWNDW HGE PFPLADHLNSTNHAIVQTL VPTELSAISMLYLDETDRV G IVAPPGYQAYY VNSVNSNIPKAC VLKNYQEMVVEG A0MK36 KRHVLYVDFSDVGWNEW HGE PFPLPDHLNATNHAVVQT VPTELSPISLLYLDEFEKV G IVAPPGYDAYY LVNSVNSNIPKAC TLKNYQDMVVDG A0MK37 KRHILYVDFSDVGWNDW HGE PFPLADHLNSTNHAIVQTL VPTELSAISMLYLDEYDK G IVAPPGYQAYY VNSVNNNIPKAC VVLKNYQEMVVEG A0SLB5 RRHPLYVDFSDVHWNDW HGE PFPLAEHLNTTNHAIVQTL VPTELSAISMLYLDEYEKY G IVAPAGYQAYY VNSVNPALVPKAC VLRNYQDMVVEG A0SLB6 QRHRLFVSFRDVGWEDWI DGE PFPLGFRLNGTNGTNHAIIQTL APTKLSGISMLYFDNNEN G IAPMGYQAYY VNSIDSRAVPKVC VVLRQYEDMVVEA A1KXV9 KRHALYVDFEDVGWNEW HGE PFPLADHLNSTNHAIVQTL VPTDLSPISLLYLDEYEKV G IVAPPGYHAFY VNSVNSNIPRAC ILKNYQDMVVEG A1XP54 QVREILVDIFQEYPEFVFYI AGC NDESLE VSTESYNTIMQIMKIKPHI E FKPSCVPLMR SQHIMDMSFQQHSH A2A2V4 HPIETLVDIFQEYPDEIEYI GGC NDEGLE VPTEESNITMQIMRIKPHQ E FKPSCVPLMR GQHIGFMSFLQHNK A2AII0 SRKPLHVNFKELGWDDWI EGV DFPLRSHLEPTNHAIIQTL VPTKLTPISILYIDAGNNV G IAPLEYEAH MNSMDPGSTPPSC VYKQYEDMVVES A2ARK2 SREALHVNFKDMGWDD EGL EFPLRSHLEPTNHAVIQIL VPTRLSPISILFIDSANNVV G WIIAPLEYEAFH MNSMDPESTPPTC YKQYEDMVVES A2AI03 KKHELYVSFRDLGWQDW EGE AFPLNSYMNATNHAIVQT AFTQLNAISVLYFDDSSNV G IIAPEGYAAYY LVHFINPDTVPRPC ILEKYRNMVVRA A4UY01 RRIIALYVDFSDVGWNDW HGE PFPLADHLNSTNHAIVQIL VPTELSAISMLYLDEHDK G IVAPPGYQAYY VNSVNNNTPKAC VVLKNYQFMVVEG A4VCG6 RPREMLVEIQQEYPDDTE AGC NDEMME TPTVTYNITLEIKRLKPLR Q HIFIPSCVVLTR HQGDIFMSFAEHSE A5GFN1 KRHELYVEFRDLGWQDW EGE AFPLNSYMNATNHAIVQT APTQLNAISVLYFDDSSNV G IIAPEGYAAYY LVHFINPETVPKPC ILKKYRNMVVRA A5GFN2 KKHELYVSFRDLGWQDW EGE AFPLNSYMNATNHAIVQT APTQINAISVYFDDSSNV G IIAPEGYAAYY LVHFINPETVPKPC ILEKYRNMVVRA A5HMF8 RRHALYVDFSDVGWNDW HGD PFPLADELNSTNHAIVQIL VPTELSAISMLYLDEYDK G IVAPPGYQAFY VNSVNSSIPKAC VVLKNYQFMVVEG A5HMF9 RRHALYVDFSDVGWNDW HGD PFPLADHLNSTNHAIVQTL VPTELSAISMLYLDEYDK G IVAPPGYQAFY VNSVNSSIPKAC VVLENYQEMVVEG A5IL80 QPRELLVDILQEYPEEVEH AGC NDEMLQ TPIEIYNITMEIKRIKPQR E IFIPSCVVLKR QQNDIFMSFTEHSA A5PII9 KRHPLYVDFSDVGWNDW HGE PFPLADHLNSTNHAIVQTL VPTELSAISMLYLDFNEKV G IVAPPGYHAFY VNSVNSKIPKAC VLKNYQDMVVEG A6N998 RRHSLYVDFSDVGWNDWI HGD PFPLADELNSTNHAIVQIL VPTELSAISMLYLDEYDK G VAPPGYQAFY VNSVNSSIPKAC VVLKYQEMVVEG A7L634 KRHPLYVDFSDVGWNDW HGE PFPLADHLNSTNHAIVQTL VPTELSAISMLYLDENEKV G IVAPPGYHAFY VNSVNSETPKAC VLKNYQDMVVEG A7LCK8 KRHELYVSFRDIGWQDW EGE AFPLNSYMNATNHAIVQT APTQLNAISVLYFDDSSNV G IIAPEGYAAYY LVHFIDPDTVPKPC ILKKYRNMVVRA A7LIT9 RRHSLYVDFSDVGWNDWI HGD PFPLADHLNSTNHAIVQTL VPTELSAISAISMLYIDEYDK G VAPPGYQAFY VNSVNSSIPKAC VVLKNYQEMVVEG A7RQI0 QRQALHVSFRKLRWQDW SGF SFPLNANMNATNHAIVQT APIELSPISVLYFDQDNNV G VIAPEGYSAFY LVHLMNFKTVFKPC VLKKYNKMVVKA A7SAY4 QRHPLYVDFTDVGWNDW TGV PYPIAKHINATNHAIVQTI IPTTLNPISILSINEFDKVV G IVAPPGYHAFY MNTVDSNVPNAC LKNYKDMVIEG A7SZJ0 RRKRMYDFRLLGWSDW EGE EYPIDNYLRPTNHATVQT TPNELSPISILYTEDGSNN G IIAPQGYDAYL IVNSLDPSIAFKAC VVYKNYKDMVVER A8E7N9 SKKPLHVNFRELGWDDW EGM DFPLRSHLEPTNHAIIQTL VPSKLSPISILYIDAGNNVV G VIAPLDYEAYH MNSMNPSNMPPSC YKQYEDMVVES A8K571 KKHELYVSFRDLGWQDW EGE AFPLNSYMNATNHAIVQT APTQLNAISVLYFDDSSNV G IIAPEGYAAYY LVHFINPFTVPKPC ILKKYRNMVVRA A8K694 KKHELYVSFRDLGWQDW DGE SFPLNAHMNATNHAIVQT APTKLNAISVLYFDDSSNV G IIAPEGYAAFY LVHLMFPDHVPKPC ILKKYRNMVVRS A8S3F5 KKHELYVSFRDLGWQDW EGE AFPLNSYMNATNHAIVQT APTQLNAISVLYFDDSSNV G IIAPEGYAAYY LVHFINPETVPKPC ILKKYRNMVVRA A8VIF8 RRHSLYVDFSDVGWNDWI HGD PFPLADHLNSTNHAIVQTL VPTELSAISMLYLDEYDK G VAPPGYQAFY VNSVNSSIPKAC VALKNQEMVVEG A9ULK0 RRHSLYVDFSDVGWNDWI HGD PFPLADELNSTNHAIVQTL VPTDLSAISMLYLDEYDK G VAPPGYQAFY VNSVNSSIPKAC VVLKNYQEMVVEG B0BMQ3 QVREILVDIFQFYPDEVEYI AGC NDESLE VPTESYNITMQIMKIKPHI E FKPSCVPLMR SQHIMDMSFQQHSQ B0CM38 RRHSLYVDFSDVGWNDWI HGD PFPLADHLNSTNHAIVQTL VPTELSAISMLYLDEYDK G VAPPGYQAFY VNSVNSSIFKAC VVLKNYQEMVVEG B0CM78 SRKALHVNFKDMGWDD EGL EFPLRSHLFPTNHAVTQTL VPTRLSPISILFIDSANNVV G WIIAPLEYEAFH MNSMDPESTPPTC YKQYEDMVVES B0FN90 RPIETLVDIFQEYPDEIEFIF GGC NDESLE VPIEEFNITMQIMRIKPHQ E KPSCVFLMR NQHIGEMSFLQHNK B0KWL9 SRKALHVNFKDMGWDD EGL EFFLRSHLEPTNHAVIQTL VPTRLSPISILFIDSANNVV G WIIAPLEYEAFH MNSMDPESTPPTC YKQYEDMVVES B0VXV3 QIREMLVSILDEHPDEVA GGC TDFSLM TATGKRSVGREIMRVDPR E HLFRPSCVTVLR KFISKIQVMQFTFHTK B0VXV4 QTREMLVSILDEHFDFVA GGC TDESLM TATGKFSVGREIMRVDPR E IILFRPSCVTVLR REISKIEVMQFIEHTE B0WCI2 QRRPLYVDFSDVGWSDWI QGD QFPIADHLNTTNHAIVQIL VPTQLSSISMLYLNEQNK G VAPPGYEAFY VNSISPSYAPKAC VVLKNYQDMTVVG B1AKZ9 KKHELYVSFRDLGWQDW EGE AFPLNSYMNATNHAIVQT APTQLNAISVLYFDDSSNV G ILAPEGYAAYY LVHFINPEIVPKPC ILKKYRNMVVRA B1MTM2 SREALHVNFKDMGWDD EGL EFFLRSHLEPTNHAVIQIL VPTRLSPISILFIDSANNVV G WIIAPLEYEAFH MNSMDPESTPPTC YKQYEDMVVES B1P8C3 RRHPLYVDFSDVGWNDW HGD FFPLADHMNSTNHAIVQT VPTELSAISMLYLDENEKV G IVAPPGYHAFY LVNSVNANIPKAC VLKNYQDMVVEG B2C4J5 PRIETLVDIFQHYPDFJHYI AGC NDESLE VPTEEFNTTMQJMRIKFHQ E FKPSCVTLMR GQHIGEMSFLQHNK B2C4J6 PRIETLVDIFQHYPDFJHYI AGC NDESLE VPTEEFNTTMQJMRIKFHQ E FKPSCVTLMR GQHIGEMSFLQHNK B2KI82 RRHSLYVDFSDVGWNDWI HGD FFPLADHLNSTNHAJVQTL VPTELSAISMLYLDEYDK G VAPPGYQAFY VNSVNSSIPKAC VVLKNYQEMVVEG B2KIC7 SRKALHVNFKDMGWDD EGL EFPLRSHLEPTNHAVIQTL VPTRLSPISLFIDSANNVV G WUAFLEYEAFH MNSMDFESTPPTC YKQYEDMVVES B2KL65 RKHELYVSFQDLGWQDW DGE SFPLNAHMNATNHAIVQT APTKLNAISVLYFDDNSNV G IIAPKGYAANY LVHLMNPEYVPKPC ILKKYRNMVVRA B2KL66 RKHELYVSFQDLGWQDW DGE SFPLNAHMNATNHAIVQT APTKLNAISVLYFDDNSNV G IIAPKGYAANY LVHLMNPEYVPKPC ILKKYRNMVVRA B2RRV6 RKHELYVSFQDLGWQDW DGE SFPLNAHMNATNHAIVQT APTKLNAISVLYFDDNSNV G IIAPKGYAANY LVHLMNPEYVPKPC ILKKYRNMVVRA B2ZP18 KKHELYVSFRDLGWQDW EGE AFPLNSYMNATNHAIVQT APTQLNAISVLYFDDSSNV G UAPEGYAAYY LVHFINPETVPKPC ULKKYRNMVVRA B3DI86 RRHSLYVDFSDVGWNDWI QGE PFPLADHLNSTNHATVQTL VPTDLSPVSLLYLDEYERV G VAPPGYHAFY VNSVNSNIPRAC ILKNYQDMVVEG B3DJ43 SKKTLHVNFRELGWDDW EGM DFPLRSHLEPTNEAIIQTL VPSKLSPISILYIDAGNNVV G VIAPLDYEAYH MNSMNPSNMPPSC YKQYEDMVVES B3FNR0 RRHELYVDFSDVHWNDW RGE PFPLAEHLNTTNHAIVQTL VPTELSAISMLYLDEYEKV G IVAPAGYQAYY VNSVNPALVPKAC VLKNYQDMVVEG B3NA13 RRHSLYVDFSDVGWDDWI HGK PFPLADEFNSTNHAVVQT VPTQLDSVAMLYLNDQST G VAFLGYDAYY LVNNMNPGKVPKAC VVLKNYQEMTVVG B3RF16 RRHSLYVDFSDVGWNDWI HGD PFPLADHLNSTNHATVQTL VPTELSAISMLYLDEYDK G VAPPGYQAFY VNSVNSSIPKAC VVLENYQEMVVEG B3RF47 SRKALHVNFKDMGWDD EGL EFPLRSHLEPTNHAVIQTL VPTRLSPISILFIDSANNVV G WIIAPLEYEAFH MNSMDPESTPPTC YKQYEDMVVES B3Y026 RRKELNVDFKAVGWNDW DGS HWPYDDHMNVTNHAIVQ VPTELSSISLLYTDEHGTV G TFAPPGYNAYY DLVNSTDPRAAPKPC VLKVYQDMVVEG B4DUF7 RKHELYVSFQDLGWQDW DGE SFPLNAEMNATNHAIVQT APTKLNAISVLYFDDNSNV G UAPKGYAANY LVHIMNFEYVPKPC ULKKYRNMVVRA B4IAU3 RRHSLYVDFQDVGWSDWI HGK PFPLADHLNSTNHAVVQT VPTQLEGISMLYLNDQRT G VAPPGYDAFY LVNNLNPGKVPKAC VVLKNYPDMTVVG B4KGU4 RRHSLYVDFQDVGWSDWI HGK PFPLADHLNSTNHAVVQT VPTQLEGISMLYLNDQRT G VAPPGYDAFY LVNNINPGKVPKAC VVLKNYQDMTVVG B4LUE0 RRHSLYVDFQDVGWSDWI HGK QFPLADHLNSTNHATVVQT VPTQLEGISMLYLNDQRT G VAPPGYDAFY LVNNLNPGKVPKAC VVLKNYQDMTVVG B4MU02 RRHSLYVDFADVGWSDWI HGK PFPLADHLNSTNHAVVQT VPTQLEGISMLYLNDQST G VAPPGYDAFY LVNNIDFGKVPKAC VVLKNYQDMTVVG B4NWQ1 RRHSLYVDFADVGWDDWI HGK PFPLADHFNSTNHAVVQT VPTQLDSVAMLYLNDQST G VAPLGYDAYY LVNNMNPGKVPKAC VVLKNYQEMTVVG B4QS48 RRHSLYVDFSDVGWDDWI HGK PFPLADHFNSTNHAVVQT VPTQLDSVAMLYLNDQST G VAPLGYDAYY LVNNMNPGKVPKAC VVLKNYQEMTVVG B4YYD6 RPIETLVDIFQEYPDEIEYI GGC NDEGLE VPTEEFNTTMQIMRIKPHQ E FRPSCVPLMR GQHIGEMSFLQHNK B5BNX6 SEKPLHVNTKDMGWDD EGL EFPLRSHLEPTNHAVIQTL VPTRLSPISILYTDSANNV G WUAELEYEAYH MHSMDEETTPPTC VYKQYFDMVVES B5BU86 HPIETLVDIFQEYPDEIEYI GGC NDEGLE VPTEESNTTMQIMRIKFHQ E FKPSCVPLMR GQHIGEMSFLQHNK B5DEK7 RPTETLVDIFQEYPDETIYI AGC NDEGLE VPTSESNVTMQIMRIKPH E FKPSCVPLMR QSQHJGEMSFLQHSR B5FW32 RRHSLYVDFSDVGWNDWI HGD FFPLADHLNSTNHAIVQTL VPTELSAISMLYLDEYDK G VAPPGYQAFY VNSVNSSIPKAC VVLKNYQEMVVEG B5FW51 SRKALHVNFKDMGWDD EGL EFPLRSHLEPTNHAVIQTL VPTRLSPISILFTDSANNVV G WUAFLEYEAFH MNSMDEESTPPTC YKQYEDMVVES B5R135 RRHALYVDFSDVGWNDW HGE PFPLADHLNSTNHAIVQTL VPTELSAISMLYLDEHDK G IVAPPGYQAYY VNSVNTNIPKAC VVLKNYQEMVVEG B6DXF1 RALERLVDIVSVYPSEVEH TGC GDENLH VPVETVNVTMQLLKIRSG E MFSPSCVSLLR DEPSYVHLTFSQHVR B6LU94 KRRKLYJRFKDVGWDDWI SGE FFPLNEHLNGTNHAVIQT APTKWSSISMLYLFDNNGD G IAPQGYMAYH LVNSLTPDSVPPAC VVLRQYEDMVVDG B6LUA7 KRRKLYIRFKDVGWDDWI SGE PFPLNEHLNGTNHAVIQT APTKWSSISMLYLFDNNGD G IAPQGYMAYH LVNSLTPDSVPPAC VVLRQYEDMVVDG B6NUD9 MRRSLQVSFHDLGWDDW AGA SFPLRSHLEPTNHAIVQTL VPTKLSPISILYIDGKDTVV G IIAPTNYDAHY VNSMNPRAVEKVC YEKYDDMVADQ B6NVZ7 RRHSLYVDFSDVGWNDWI HGE PFPLADHLNSTNHAIVQTL VPTDLSPISMLYLNENDQ G VAPPGYQAYY VNSVNPLAVPKAC VVLKNYQDMVVEG B6NVZ8 RRLHLYVDFREVGWQDW AGD FFPLNEKLNGTNHAIIQTL APTALSJSMLYFDESGNV G IIAPPGYHAYY VNTVAPAAVPRPC VLRQYEDMVVEG B6F6C2 MRRSLQVSFHDLGWDDW AGA SFPLRSHLEPTNHAIVQTL VPTKLSPISILYIDGKDTVV G UAPTNYDAHY VNSMNPRAVEKVC YKKYDDMVADQ B6SCR4 QRHPLYVDFSEVGWNDWI KGE PFHJADHLNTTNHAIVQTL VPTTLDAISMLFMNEHSK G VAPPGYQGFY MNSVNPNNVPPAC VVLKNYQDMVVDG B6SCR5 QRHPLYVDFSEVGWNDWI KGE PFPIADHLNTTNHAIVQTL VPTTLDAISMLFMNEHSK G VAPPGYQGFY MNSVNPNNVPPAC VVLKNYQDMVVDG B6VAE7 KPRETVVRIGDEYPSLTSQ GGC NDESLE VPTEEANTTMEVMSVSS D RESPPCVSVMR TGSNPGMQNMQFVEHLR B6VAE8 KPRETVVRISDEYPSLTSQ GGC NDESLE VPTEEANTTMEVMSVSS D RESPPCVSVMR TGSNPGMQNMQFVEHLH B6ZHB6 HRRRLHVNFKEMGWDD DGA DFPIRSHLEPTNHAITQTLI VPTRLSPISLYIDSANNVV G WUAFLEYDAYH NSMDPESTPPTC YKQYEDMVVES B7NZT8 SRKALHVNFKDMGWDD EGL EFPLRSHLEPTNHAVIQTL VPTRLSPISLFIDSANNVV G WIIAPLEYEAFH MNSMDPESTPPTC YKQYEDMVVES B7QHX4 RRFPLRVEESHVGWNDWI HGV PFPLPDHLNGTNHAIVQT VPTELSPVSLLYVDAFHRV G VAPPSYEAYY LVNSMRAGGVPNAC VLKNYQDMVVEG B7ZPR8 RRHSLYVDFSDVGWNDWI HGD PFPLADHLNSTNHAJVQTL VPTELSAISMLYLDHYDK G VAPPGYQAFY VNSVNSSIPKAC VVLKNYQEMVVEG B7ZQN5 SKKPLHNFKELGWDDWI EGV DFPLRSHLEPTNHAIIQTL VPTKLTPTSILYIDHYDK G IAPLEYEAHH MNSMNPGSTPPSC VVLKNYQEMVVEG B7ZRN7 RRFPLYVDESDVGWNDW HGE PFPLADHLNSTNHAIVQTL VPTELSAISMLYLDENEKV G IVAPPGYHAFY VNSVNTNIPKAC VLKNYQDMVVEG B8A4Z0 RPREMLVEIQQEYPDDTE AGC NDEMME TPIVIYNITLEIKRLKPLR Q HJFJPSCVVUTR HQGDIFMSGSFHSE B8XA45 RRHALYVDFSDVGWNDW HGE PFPLADHLNSTNHAJVQTL VPTELSAISMLYLDEHDK G IVAPPGYQAYY VNSVNTNIPKAC VVLKNYQEMVVEG B8XRZ3 RRIIALYVDFSDVGWNDW HGE PFPLADHLNSTNHAJVQTL VPTELSAISMIYLDEHDK G IVAPPGYQAYY VNSVNTNIPKAC VVLKNYQEMVVEG B8YPW1 QRRPLFVDFAEVGWSDWI QGD PFPLADHLNGTNHAJVQT IPTQLSPISMIYMDEHNQ G VAPPGYEAYT LVNSVDPALVPKAC VALKNYQDMMVMG B9EI18 KRHELYVSFRDLGWQDW DGE SFPLNAHMNATNHAIVQT APTKLNAISVLYFDDSSNV G IIAPEGYAAFY LVHLMFPDHVPKPC ILKKYRNMVVRS C0H3A5 RRHALYVDFSDVGWNEWI HGE PFPLADHLNSTNHAJVQTL VPTELSPISLLYLDHYHKVL G VAPPGYHAFY VNSVNSNIPRAC LKNYQDMVVEG C0K3N1 QPRETLVSILEEYPDKISKI GGC SDESLT TSVGERTVELQMVWVIPK E FRPSCVAVLR TLSSKIKVMKFREHTA C0K3N2 QTRETLVSILEEHPHELSHL GGC SDESLT TSTGKRSVGREIMRVDPH E FKPSCVTVLR KETSKIEVMQFTEHTD C0K3N3 QTREMLVSILDEYPSEVAH GGC TDESLT TATGKRSVGREIMRVDPR E LFRPSCVTLVR KGTSKIEVMQFTEHTE C0K3N4 RPLETMVDIFQEYPDEVEY GGC NDEALE VPTELYNVTMEIMKLKPY E ILKPPCVALMR QSQHIHPMSFQQHSK C0K3N5 RPVETMVDITQEYPDEVE GGC NDEALE VPTEVYNVIMEIMKLKPF E YIFKPSCVALMR QSQHIEPMSFQQHSK C0K3N6 QTRETLVPILKFYPDFVSH GGC SDESLT TATGKHSVGREIMRVDPH E LFKPSCVPVLR KGTSKMEVMQFKEIITA C0K3N7 RPIETMVDIFQDYFDEVEY GGC NDEALE VPTELYNVTMEIMKLKPY E ILKFPCVALMR QSQHJHPMSFQQHSK C0K3N8 QAREILVPILQEYPDEISDI SGC TDESLK TPVGKHTVDLQIMRVNPR E FRPSCVAVLR TQSSKMEVMKTIHHTA C0K3N9 QTRETLVSILQEHPDEISDI SGC TDESMK TPVGKHTVDLQIMRVNPR E FRPSCVAVLR THSSKMFVMKMEHTA C1BJY6 RPRELLVEILQEYPEEVEHJ AGC NDEMLQ TPTSTHNTTMEIKRIKPQR E YIPSCVVLTR QQNDIFMSFTEHNS C3KGR8 RPMEQLVDEQEYPGEVE SGC MDENLF QASLKSNTTLEVMRIHPMI E YIYMPACVPLWR SMHHVLLTFVEHQR C3PT60 SRKALHVNFKDMGWDD EGL EFPLRSHLFPTNHAVJQTL VPTRLSPISLLFIDSANNVV G WIIAPLEYEAFH MNSMDPESTPPTC YKQYEDMVVES C3SB59 KREPLYVDFSDVGWNDW HGE PFPLADHLNSTNHAIVQTL VPTELSAISMLYLDENEKV G IVAPPGYHAFY VNSVNSNIPKAC VLKNYQDMVVEG O13107 RRHALYVDFSDVGWNDW HGE PFPLADHLNSTNHAVQTL VPTELSAISMLYLDETDRV G IVAPPGYQAYY VNSVNTNIPKWC VLKNYQEMVVEG O13108 RRHALYVDFSDVGWNEWI HGE PFPLADHLNSTNHAIVQTL IPTELSPISLLYLDEYEKVI G VAPPGYHAFY VNSVNSNIPKAC LKNYQDMVVEG O13109 RRHSLYVDFSDVGWNDWI QGE PFPLADHLNSTNAMVQT VPTDLSPCSLLYLDEYERV G VAPPGYHAFY LVNSVNSNIPRAC ILKNYQDMVVEG O19006 KREPLYVDFSDVGWNDW HGE PFPLADHLNSTNHAIVQTL VPTELSAISMLYLDENEKV G IVAPPGYHAFY VNSVNSKIPKAC VLKNYQDMVVEG O42303 NRKQLHVNFKEMGWDD DGV DFPIRSHLFPTNHAIIQTL VPTRLSPISILYIDSANNVV G WIIAPLEYEAFH MNSMDFRSTPPTC YKQYEDMVVES O42571 QVREILVDIFQEYPDEVEYI AGC NDESLE VPTECYNTTMQIMKIKPHI E FKPSCVPLMR SQHIMDMSFQQHSQ O42572 QVREILVDIFQEYPDEVEYI AGC NDESLE VPTECYNTTMQIMKIKPHI E FKPSCVPLMR SQHIMDMSFQQHSQ O46564 KREPLYVDFSDVGWNDW HGE PFPLADHLNSTNHAIVQTL VPTELSAISMLYLDENEKV G IVAPPGYHAFY VNSVNSKIPKAC VLKNHYQDMVVEG O46576 RRHALYVDFSDVGWNDW HGD PFPLADHLNSTNHAIVQTL VPTELSAISMLYLDEYDK G IVAPPGYHAFY VNSVNSSIPKAC VVLKNYQEMVVEG O57573 RRHALYVDFSDVGWNEWI HGE PFPLADHLNSTNHAIVQTL IPTELSPISLLYLDEYEKVI G VAPPGYHAFY VNSVNSKIPKAC LKNYQDMVVEG O57574 RRHALYVDFSDVGWNDW HGE PFPLADHLNSTNHAJVQTL VPTELSAISMLYLDETDRV G IVAPPGYQAYY VNSVNTNIPKAC VLKNYQEMVVEG O73682 KTRELLVDJJQEYPDEIEH AGC NDEALE VPTETRNVTMFVLRVKQR E TYIPSCVVLMR VSQENFQLSFIEHTK O73682-2 KTRELLVDIIQEYPDEIEH AGC NDEALE VPTEIRNVTMEVLRVEQR E TYIPSCVVLMR VSQHNFQLSFTEHTK O73818 RRHSLYVDFSDVGWNDWI HGD PFPLADHLNSTNHAJVQTL VPTELSAISMLYLDEYDK G VAPPOYQAFY VNSVNASIPKAC VVLKNYQEMVVEG O76851 QRQDLYVDFSDVNWDDW NGE PFPLAEYMNATNHAIVQT VPIELSPIAMLYVDECELV G TVAPHGVHAFY LVNSVDPSLTPKPC VLKTYQQMAVEG O77643 RPJSTLVDJFQRYPDEJEFTF GGC NDESLE VPTEEFNTTMQIMRIKPHQ E KPSCVPLMR SQHIGEMSFLQHNK O88911 RPIEILVDIFQEYFEIEYI AGC NDEALE VPTSESNVTMQTCK S FKPSCVPLMR O93369 RRHALYVDFSDVGWNEWT HGE PFPLPDHLNSTNHAIVQTL IPTELSPISLLYLDEYEKVI G VAPPGYIIAFY VNSVNANIPKAC LKNYQDMVVEG O93573 SRKPLIIVNFKELGWDWI EGV DFPLRSIILIPTNHAIIQTL VPSKLSPISILYIDSGNNVV G TAPLDYFAYH MHSMDPESTPPSC YKQYPDMVVET O96504 RRHSLYVDFSDVGWNDWI HGE PFPLADHLNSTNHAIVQTL VPTDLSPISMLYLNENDQ G VAPPGYQAYY VNSVNPLAVPKAC VVLENYQDMVVEG O97390 RRKGLNVDFKAVGWNDW DGS HWPYDDEMNVINHAIVQ VPTELSSLSLLYIDEHGAV G TFAPPGYNAYY DLVNSJDPRAAPKPC VLKVYQDMVVEG P07713 RRHSLYVDFSDVGWDDWI HGK PFPLADHFNSTNHAVVQT VPTQLDSVAMLYLNDQST G VAPLGYDAYY LVNNMNPGKVPKAC VVLKNYQEMTVVG P12643 KREPLYVDFSDVGWNW HGE PFPLADELNSTNIIAIVQIL VPIELSAISMLYLDENEKV G IVAPPGYHAFY VNSVNSKIPKAC VLKNYQDMVVEG P12644 RRHSLYVDFSDVGWNDWI HGD PFPLADHLNSTNHAIVQTL VPTELSAISMLYLDEYDK G VAPPGYQAFY VNSVNSSIPKAC VVLENYQEMVVEG P15691 KPETTLVIFQEYPDEEIFIF GGC NDESLE VPTEEFNIIMQMRIFPEQ E KPSCVPLMR SQHIGFMSFLQHNK P15691-2 RPIETLVDIFQEYPDETEFTF GGC NDESLE VPTEEFNTTMQMRIKPHQ E KPSCVPLMR SQEIGEMSFLQILNK P15692 HPIEILVDIFQEYPDEIEYI GGC NDEGLE VPTEESNTTMQIMRIKPHQ E FKPSCVPLMR GQHIGFMSFLQHNK P15692-10 HPIETLVDIFQEYPDEJEYI GGC NDEGLE VPTEESNTTMQJMRIKPHQ E FKPSCVPLMR GQHIGEMSFLQHNK P15692-2 HPIETLVDIFQEYPDEIEYI GGC NDEGLE VPTEESNIIMQMRIEPHQ E FKPSCVPLMR GQHIGEMSFLQHNK P15692-3 HPIETLVIFQEYPDEIEYI GGC NDEGLE VPTEESNTTMQIMRIKPHQ E FKPSCVPLMR GQHIGEMSFLQHNK P15692-4 HPIEILVDIFQEYPDEIEYI GGC NDEGLE VPIEESNTTMQIMRIKPHQ E FKPSCVPLMR GQHIGEMSFLQHNK P15692-5 HPIETLVDIFQEYPEIEYI GGC NDEGLE VPTEESNTTMQJMRIKPHQ E FKPSCVPLMR GQHIGEMSFLQHNK P15692-6 HPIETLVDIFQEYPDEIEYI GGC NDEGLE VPTEESNIIMQMRIKPHQ E FKPSCVPLMR GQHIGEMSFLQHNK P15692-7 HPIETLVDIFQFYPDEIEYI GGC NDEGLE VPTEESNTTMQMRIKPHQ E FKPSCVPLMR GQHIGEMSFLQHNK P15692-8 HPIEILVDIFQEYIDEIEYI GGC NDEGLE VPIEESNTTMQIMRIKPHQ E FKPSCVPLMR GQHIGEMSFLQHNK P15692-9 HPIETLVDIFQEYPDEIEYI GGC NDEGLE VPTEESNTTMQJMRTKPHQ E FKPSCVPLMR GQHIGEMSFLQHNK P16612 RPEIILVDIFQEYPDEEIYI AGC NDEALE VPTSESNYIMQIMRIKPH E FKPSCVPLMR QSQHJEMSFLQHSR P16612-2 RPIETLVDIFQEYPDEIEYI AGC NDEALE VPTSESNVTMQIMRIKPH E FKPSCVPLMR QSQHIGEMSFLQHSR P16612-3 RPIETLVDIFQEYPDEIEYI AGC NDEALE VPTSESNVTMQIMRIKPH E FKPSCVPLMR QSQHIGEMSFLQHSR P16612-4 RPIETLVDIFQRYPDEIEYI AGC NDEALE VPTSESNVTMQIMRJKPH E FKPSCVPLMR QSQEIGEMSFLQHSR P18075 KRHELYVSFRDLGWQDW EGE AFPLNSYMNATNHAIVQT APTQLNAISVLYFDDSSNV G HAPEGYAAYY LVHFINPETVPKPC JLKKYRNMVVRA P20722 KRHELYVSFQDLGWQDW DGE SFPLNAHMNATNHAJVQT APTKLNAISVLYFDDNSNV G HAPKGYAANY LVHLMNPEYVPKPC ILRKYRNMVVRA P21274 KREPLYVDFSDVGWNDW HGE PFPLADELNSTNHAIVQIL VPIELSAISMLYLDENEKV G TVAPTGYHAFY VNSVNSKIPKAC VLKNYQDMVVEG P21275 RRHSLYVDFSDVGWNDWI HGD PFPLADHLNSTNHAIVQTL VPTELSAISMLYLDEYDK G VAPPGYQAFY VNSVNSSIPKAC VVLENYQEMVVEG P22993 KRHELYVSFRDLGWQDW DGE SFPLNAHMNATNHAIVQT APTKLNAISVLYFDDSSNY G HAPEGYAAFY LVHLMFPDHVPKPC JLKKYRNMVVRS P22004 RKHELYVSFQDLGWQDW DGE SFPLNAHMNATNHAJVQT APTKLNAISVLYFDDNSNV G HAPKGYAANY LVHLMNPEYVPKPC ILRKYRNMVVRA P23359 KKHELYVSFRDLGWQDW EGE AFPLMNSYMNATNILAIVQT APTQLNAISVLYFDDSSNV G UAPEGYAAYY LVHFINPDTVPKPC ILKKYRNMVVRA P25763 RRHPLYVDFSDVGWNDW HGE PFPLADHLNSTNHAIVQTL VPTELSAISMLYLDENEKV G IVAPPGYHFY VNSVNTNTPKAC VLKNYQDMVVEG P26617 RPEIMLVDIFQEYPDEIEYI GGC NDESLE VPTEEFNIIMQMRIKPHQ E FKPSCVPLMR GQHIGEMSFLQHSK P30884 RRHPLYVDFSDVGWNDW HGE PFPLADHLNSTNHAJVQTL VPTELSAISMLYLDFNEKV G IVAPPGYHAFY VNSVNTNIPKAC VLRNYQDMVVEG P30885 RRHSLYVDFSDVGWNDWI HGD PFPLADHLNSTNHAIVQTL VPTELSAISMLYLDEYDK G VAPPGYQAFY VNSVNSSIPKAC VVLRNYQEMVVEG P35621 KPRRLYIDFKDVGWQDWI HGE PFPLSESLNGTNHAILQTL VPIKLSPISMLYYDNNDNV G IAPQGYLANY VHSFDPKGTPQPC VLRHYFDMVVDF P43026 SRKALHVNFKDMGWDD EGL EFPLRSHLEPTNHAVJQTL VPTRLSPTSILFIDSANNVV G WIIAOLEYEAFH MNSMDPESTPPTC YKQYEDMVVES P43027 SRKALHVNFKMGWDD EGL EPPLRSHLEPTNHAVIQTL VPIRLSPISILFIDSANNVV G WUSPLEYEAFH MNSMDPESTPPTC YKQYEUMVVES P43028 SRKPLHVNFKELGWDDWI EGV DFPLRSHLEPTNHAJJQTL VPTKLTPISILYIDAGNNV G IAPLHYEAYE MNSMDPGSTPPSC VYKQYEDMVVES P43028 SRESLHVDFKELGWDDWI EGV DFPLRSHLHPINEAIIQTL VPARLSPISILYIDAANNVV G IAPLDYEAYH LNSMAPDAAPASC YKQYEDMVVRA P43029-2 SRKSLHVDFKEKGWDDWI EGV DFPLRSHLRPTNHAIIQTL VPARLSPISILYIDAANNVV G IAPLDYEAYH LNSMAPDAAPASC YKQYHDMVVEA P48969 KRKNLFVNFHDLDWQEWI QGE AFPLNGHANATNHAIVQT APIKLSPITVLYYDDSRNV G IAPLGYVAFY LVHHMSPSHVPQPC VLKKYKNMVVRA P48970 QRHRLFVSFRDVGWFNWI DGE PFPLGFRLNGTNHAUQTL APTKLSGISMLYFDNNEN G IAPMGYQAYY VNSIDNRAVPKVC VVLRQYEDMVVEA P49001 KRHPLYVQFSDVGWNDW HGE PFPLADHLNSTNHAIVQTL VPTELSAISMLYLDENEKV G IVAPPGYHAFY VNSVNSKJPKAC VLKNYQDMVVEG P49003 KKHELYVSFRDLGWQDW DGE SFPLNAHMNATHAJVQT APTKINAISVLYFDDSSNV G EIAPEUYAAFY LVHLMFPDHVPKPC ILRKYRNMVVRS P49151 RPIETLVDIFQEYPDEIEYI GGC NDEGLE VPTEEFNTTMQIMRIKPHQ E FKPSCVPLMR GQHIGFMSFLQHNK P49763 RALSRLVDVVSRYPSEVEH TGC GDENLH VPVETANVTMQLJKIRSG E MFSPSCVSLLR DRPSYVELIFSQHVR P49763-2 RALERLVDVVSEYPSEVEH TGC GDENLH VPVETANVTMQLLKIRSG E MFSPSCVSLLR DRPSYVHLTFSQHVR P49763-3 RALERLVVVSEYPSEVEH TGC GDENLH VPVETANVTMQLLKIRSG E MFSPSCVSLLR DRPSYVELTFSQHVR P49764 RPMEKLVYILDEYPDEVS SGC GDEGLH VPIKTANTTMQILKIPPNR E HIFSPSCVILSR DPHFYVEMTFSQDVL P50412 RPIFTLVDJFQRYPDFJFFIF GGC NDESLE VPTEEFNTTMQJMRIKPHQ E KPSCVPLMR SQHIGEMSFLQHNK P55106 SKKPLHVNFKELGWDDWI EGV DFPLRSHLHPINEAIIQTL VPTKLTPISILYIDAGNNV G IAPLRYRAYH MNSMUPGSTFPSC VYNFYFEMVVES P67860 RPTETMVDIFQDYPDEVEY GGC NDEALE VPTELYNVTMEIMKJKPY E ELKPPCVALMR QSQHEEPMSFQQHSK P67860-2 RPIETMVDIFQDYPDEVEY GGC NDEALE VPTELYNVIMEIMLKPY E ILKPPCVALMR QSQHIHPMFQQHSK P67860-3 RPIETMVDIFQDYPDFVFY GGC NDEALE VPTELYNVTMFJMKLKPY E ILKPPCVALMR QSQEIHPMSFQQESK P67861 QIRETLVSILQEEPDEISDI SGC TDESMK TPVGKETADIQIMRMNPR E FRPSCVAVLR THSSKMPEVMKFMPHTA P67862 QTRETLVPILKEYPDEVSH GGC SDESLT TATGKHSVGREIMRVDPH E LFKPSCVPVLR KGTSKMEVMQFKGHTA P67863 QAREILVPILQEIYDEISDI SGC TUESLK TPVGKHIVDLQIMRVNPR E FRPSCVAVIR TQSSKMFVMKFTFHTA P67964 RTTETLVDIFQFYPDRVRYI AGC GDEGLE VPVDVYNVTMEIARIKPH D FRPSCVPLMR QSQEIAEMSFLQHSK P67965 RTIETLVDIFQFYPDEVEYI AGC GDEGLE VPVDVYNVIMEIARIKPH D FRPSCVPLMR QSQHJAHMSFLQHSK P67965-2 RTIETLVDIFQFYPDEVEYI AGC GDEGLE VPVDVYNVTMEIARJKPH D FRPSCVPLMR QSQHLAHMSFLQHSK P67965-3 RTIEILVDIFQHYPDEVEYI AGC GDEGLE VPVDVYNVTMEIARIKPH D FRPSCVPLMR QSQHIAHMSFLQHSK P67965-4 RTIETLVDIFQRYPDRVRYI AGC GDEGLE VPVDVYNVTMEIARIKPH D FRPSCVPLMR QSQEIAEMSFLQHSK P82475 QAREILVSILQEYPDEISDI SGC TDFSLK TPVGKETVDMQIMRVNP E FRPSCVAVLR RTQSSKMFVMKFTRHTA P83906 RPVETMVDIFQHYPDEVE GGC NDEALE VPTEMYNVTMEVMKLKP E YIFKPSCVALMR FQSQHIHFVSFQQHSK P83942 QAREILVSILQEYPDEISDI SGC TDESLK TPVGKHIVDLQIMRVNPR E FRPSCVAVLR TQSSKMFVMKFTRHTA P85857 SKKALHVNFKELGWDDW EGV DFPLRSHLEPTNHAJJQTL VPTKLSPISILYIDSGNNVV G IIAPLDYEAYH MNSMDPNSTPPSC YEQYEDMVVEQ P87373 KRHELYVSFRDLGWQDW DGE SFPLNAHMNATNHAIVQT APTKLNAISVLYFDDSSNV G IIAPEGYAAFY LVHLMFPDHVPKPC ILKKYRNMVVRS P91706 RRHSLYVDFSDVGWDDWI HGK PFPLADHFNSTNHAVVQT VPTQLDSVAMLYLNDQST G VAPLGYDAYY LVNNMNPGKVPKAC VVLKNYQEMTVYG P91720 RRHSLYVDFQDVGWSDWI HGK QFPLADHLNSTNHAVVQT VPTQLEDISMLYLNDQRT G VAPPGYDAYY LVNNLNPGKVPKAC VVLKNYQDMTVVG Q00731 RPIHTLVDJFQHYPDFJRYI AGC NDEALE VPTSESNTTMQJMRJKPHQ E FKPSCVPLMR SQHIGEMSFLQHSR Q00731-2 RPEITLVDIFQEIYPEEIYI AGC NDEALE VPTSESNHMQIMRIKPHQ E FKPSCVPLMR SQHIGFMSFLQHSR Q00731-3 RPIETLVDIFQEYPDETEYI AGC NDEALE VPTSESNITMQIMIRIKPHQ E TKPSCVPLMR SQHIGEMSFLQHSR Q00731-4 RPRTLVDEFQSYPDEFYI AGC NDEALE VPTSESNITMQVGTCTG L FKFSCVFLMR DGAGAGGERRTVVQGGA KKHELYVSFGDLGWQDW DGE SFPLNAHMNATHHAJVQT LEGCL Q04906 BAPKDYAANY LVHLMNPEYVPEPC APTKINAISDLYFDDNSMV G RRHSLYVDFSVDGWNDWI HGD FFPLADHLNSTNHAIVQTL RAKYRNMVVRA Q66826 VAPPQYQAFY VNSVHSSIPKAC VPTELSAISMEYLDEYDK G QVREILVDIFQFYPDEVEYE AGC NDEALE VVIKNYQEMVVEG Q07081 PKPSCVPLMR VPTESYNITMQIMKIKPHI G QRHPLYCDFTDVGWNDW TGV PYPIAKHLNAYNHAIVQD SQHIMDMSFQQHSQ Q0P6N0 IVAPPGYHAFY MNTVDSNVPNAC IPTILNPISILSLNEFDKVV G KPREMLVEIQQEYPDDTE AGC NDEMME LKNYKDMVIEG Q0QYI0 HIFIPSCVVLTR TPTVTYNITLEIKPLKPER G QRRPLYVDFEDVGWSDWI HGD QFPIADHLNTINHAIVQTL HQGDIFMSFAEHSE Q17JZ3 VAPPGYEAYY VNSEPSLAPKAC VFTQLESSISMLYLNEQNK G RMETLVIGFQEYPDEIEFIF GGC NDESLE VVIJNYQDMTVVG Q15I09 KPSCVFLMR VPTEEFNTMQIMRIKPHQ H KPREMLYESQQEYPDDTE AGC NDEMME SQHIGEMSFLQHNK Q1ANE8 HIFIFSCYVLTR TPIVTYHITLPIKRLSPLR Q RPPEMLVEIQQEYPDDTE AGC NDEMME HQGDIFMSFAEHSE Q1ECU5 HIPIPSCVVLTR TPTVTYNITLEIKRIKPLR Q KKRSLYVSFRELGWQDWI NGE SFPLNAHMNATNHAIVQT HQGDIFMSFAEHSE Q1PHR6 IAPDGYSAFY LVHLMDFEAVPKPC AFTKLNAEVLYFDDSSNV G KRHELYVDFNDVGWNDW HGE PFPIAEHLNSTNHAIVQTL ILKKYRNMIVKS Q1PHR7 IVAPFGYHAFY VNSVSPDSVPKC VPIDLSPISMLYLDEFDKV G RRHSLYVDFSDVGWDDWI HGK PFFLADHFNSTNHAVVQT VLKNYQDMVVSG Q1WEY6 VAPLGYDAYY LYNNMNTGKVPKAC VPTQLDSVAMLYLNDQST G RRHSLYVDFSDVGWDDWI HGK PFPLADHFNSTNHAVVQT VVLKNYQEMTVVG Q1WKY7 VAPLGYDAYY LVNNMNPGKVPKAC VFTQLDSVAMLYLNDQST G RRHSLYVDFSDVGWDDWI HGK FFPLADHFNSTNHAVVQT VVLKNYQEMTVVG Q1WKY8 VAPLGYDAYY LVNNMNPGKVPKAC VFTQLDSVAMLYLNDQST G QRRFLFVDFADVGWDDWI QGD PFPLSDHLNGTNHATVQTL VVLKNYQDMMVVG Q15211 VAFHGYDAYY VNGVNPAAVPKAC VFTQESSEMLYMDEVNN G VVLKNYQDMMVVG Q26468 PRHPLYVDFKEVGWDDW HGD PFPLSDHMNGTNHATVQT IPTQLTMEMLYLDEESKV G IVAPPGYEQWY LMNSMSKGLVPKAC VLKNYHEMAVVG Q27W10 QRGALHVSFRKLRWGDW SGE SFPLNANMMNATNHAIVQT APTELSFISVLYFDQDNNV G VLAFEGYSAFY LVHLMNPKTVPKPC ALKKYNKMVVKA Q29607 RRHSLYVDFSDVGWNDWI HGD FFPLADHLNSTNHAIVQTL VPTELSAISMLYLDEYDK G VAFFGYQAFY VNSVNSSIPKAC VVIKNTDEMVVEG Q35H1 RRHSLYVDFSDVGWHDWI HGD PFTLADHLNSTNHAIVQTL VPTELSAISMEYLDEYDK G VAFFGYQAFY VNSVNSSIPKAC VVLKNYQEMVVEG Q2KT33 RRHSLYVDFFSDVGWHDWI HGD PFFLADHLNSTNHAIVQTL VPTELSAISMEYLDEYDK G VAFFGYQAFY VNSVNSSIPKAC VVLKNYQEMVVEA Q2NKW7 SREALHVNFKDMGWDD EGL EFPLRSHLEPTNHAVTQTL VPTRLSMSILFIDSANNVV G WEAPLEYEAFH MNGMDPESTPFIC VKQYEDMYVES Q2VEW5 RRHFLYVDFSDYGWNDW QGD FFPLTDHLNSTNHAIVQTL VFTELSAISMLYLDSYDK G IVAAPFCYHAFY VNSVNSSIPRAC VVLKNYQEMVVEG Q2WBX0 RRHFLYVDFSDYGWNDW NGE QFPLPFYNATNHAIVQTL VPTELSAISMLYVDEHDK G IYAPFGYRAYF YHSVNFEAVFRFC VTLKNYQDMVVVG Q330H7 PRKRMYVDFRLLGWSDW EGE KYPADHYLRPTNHATVQT TPNEDSFISILYTEDGSHN G HARQGYDAYL IVNSLDPSIAKAC VVYKNYKDMVVER Q330K6 QTREMCVPILKEYNEVS GGC SDESLT TATGKESVGREVMRVDF G HLFKPSCVPVLK HKGTSKIEYMQFKEHTA Q38KY2 RPRELLVDIYGEYPEEIEH GGC NDEALE VTVATRNYTLEVKKVKLH D TYIPSCYVLMR VTQHNFLLSFTEHTS QHSL9 RRHMLYVDFSDVGWNDW HGE PFFLADHLNSTNHAIVQTL VPTELSFSMLYLDEADEV G IVAPPGYQAYY VNSVNFQLVFKAC VLKHYQDMYYEG QHSM3 SRKALHVMFSDMGWDD EGL EFFLESHLEFTNHAVIQTL VPTKLSPISEFIDSANNVV G WEAPLEYEAPH MNSMDFESTPPTC YEQYEDMVVES Q3ULR1 RRHSLYVDFSDVGWNDWZ HGD EFFLADHLSTNHAIVQTL VPTELSAISMLYLDEYDK G VAPPGYQAFY VNSVNSSIFKAC VVLKNYQEMVVEG Q3UXB2 KKHELYVSFQDLDWQDW DGE SFPLNAHMNATNHAIVQT APIKLNAISVLYFGDNENY G MAPKGYAAFY LVHLMNFFYVPKAC ILKKYRNMVVRA Q3VIM KKHELYVSFQTILDWQDW HGE SEPLNAHMNATNHAIQT APIKLNAISVLYFGDNENY G IIAFEGYAAFY LVIEMFPDHVPKFC ILKKYRNMVVRS Q496PS KEHELYVSFRDEGWQDW DGE SFFLNHMNATNHAIVQT APIKLNAISVLYFGDNENY G ILAFEGYAAFY LVHLMFFIAHVPKFC ILKKYRNMVVRS Q496P9 KRHFLYVDFSDYDWNDW DGE PSPLADHLNSTNHAIVQTL VPTELSAISMLYLDENSKV G IYAFFGYHAFY VNSVNSKIPKAC VEKNYGDMVVEG Q497W8 KRHFLYVDFSDYDWNDW NGE PFPLADHLINSTNHAIVQTL VPTELSAISMLYLDENSKV G IYAFFGYHAFY VNSVNSKIPKAC VVLRLYEDMVVEA Q4H2P7 QRIHSMWVDFEEMGWGD AGE PFFLSGKLNGTNHHAMLM VPTELSAISMLYLDENSKV G WYIAPEAFQSYE TMMNSVDFSHTPMPC VVLRLYEDMVVEA Q4ICQ2 PKHALYVSFQDLDWQDW DGE SFFLNAHMMATNHAIVQT APTKLNAISVLYFDDHGMV G ILAPKGYAANY LVHEMNFEYVPKPC ILKKYRNMVVEA QNLEV0 RRHSLYVDFSDVQWNDWI HGD FFPLADHLNSTNHAIVQTL VPTELSAISMLYLDEYDK G VAPPGYQAFY VNSYNSSIPKAC VYDKNYQEMVVEG Q4R5W6 KKHELYVSFRDLGWQDW DGE SFFLNAHMNATNHAIVQT APTKLNAISVLYFDDSSNV G IIAPEGYAAFY LVHLMFPDHVPKPC ILKKYRNMVVRS Q4RLYS KTIEKLVEVVQEYPTEVEY AGC GDEKLE HPTTITNVIMQLLKIRFS E IYSPSCVPLVR EPHKEYVHMTFVEHQT Q4RMK1 RRHSLYVDFSDVGWNDWI HGD PFPLADHLNSTNHAIVQTL VPTELSAISMLYLDEHDK G VAPPGYQAYY VNSVNSNIPKAC VVLKNYQEMVVEG Q4RQB0 KKHELYVSFRDLGWQDW DGE AFPLNAHMNTNHAIVQT APTKLNAISVLYFDDSSNV G IIAPEGYAAFY LVHLMFPDNVPKPC UIKKYRNMVVRS Q4SCW7 QPMEQLVDVEQFYPGELE SGC GDEHLE QPTLESNVTLQVIKIQQTV E YIYMPSCVPLKR VSMHYVEITFVEHOR Q4SSW6 SRKALHVNFKELGWDDWI EGV DEPLRSHLEPINEAIIQTL VPTKLSPISILYIDSGNNVV G IAPLDYEAHH MNSMDPNSTFPSC YKQYEDMVVEQ Q4SV40 QPRDVLVDVFQAYPEDTE GGC NDEGKE VPAESRNVTLQLQRFRPR V HIYTPSCVVLKR VIKEVVDLSFIEHVL Q4SZ19 KARRLYIDFKDVGWQDWI HGE PFPLSDSLNGTNHAILQTL VFIRLSFISMLYYDNNDNV G IAPQGYMANY VHSLDPHGTPQPC VLRHYQDMVVDE Q4U4G1 KPRFMVFRVHDEYPTLTS GGC NDESLE VPTEEANVTMQLGASVS D QRFNPPCVILMR GGNGMQHLSFVEHKK Q4VBA3 RKHELYVSFQDLGWQDW DGE SFPLNAHMNATNHAIVQT APTKLNAISVLYFDDNSNV G IIAPKGYAANY LVHLMNPEYVPKPC ILKKYRNMVVRA Q53XC5 RRHSLYVDFSDVGWNDWT HGD PFPLADHINSTNHAJVQTL VPTELSAISMLYLDHYDK G VAPPGYQAFY VNSVNSSIPKAC VVLKNYQEMVVEG Q53XY6 RALERLVDVVSEYPSEVEH TGC GDENLH VPVETANVIMQLLKIRSG E MFSPSCVSLLR DRPSYVELTFSQHVR Q540I2 RTIETLVDIFQEYPDEVHYI AGC GDEGLE VPVDVYNVTMEIARKPH D FRPSCVFLMR QSQEIAEMSFLQHSK Q541S7 RPIETLVDIFQEYPDEIEYI AGC NDEALE VPTSESNVTMQIMRIKPH E FKPSCVPLMR QSQHJGEMSFLQHSR Q544A5 RPMEKLVYILDEYPDEVS SGC GDEGLM VPIKTANTIMQILKIPPNR E HIFSFSCVLLSR DPHFYVEMTFSQDVL Q58E94 RRHPLYVDFSDVGWNDW HGE PFPLADELNSTNIIAIVQIL VPTELSAISMLYLDENEKV G IVAPPGYHAFY VNSVNTNIFKAC VLKNYQDMVVEG Q58G88 QRHSLYVSFREVGWQDWT SGE PFPLNDRLNGTNHAIIQIL APTKLSAISMLYFDNDEN G IAFMGYQAYF VNSMDPSSVFKVC VVLRQYEDMVVEA Q58FH5 HPIETLVDIFQEYPDEIEYI GGC NDEGLE VPTEESNIIMQIMRIKPEQ E FKPSCVPLMR GQHIGEMSFLQHNK Q5I4I9 RRHSLYVDFSDVGWNDWI HGD PFPLADHLNSTNHAJVQTL VPTELSAISMLYLDHYDK G VAPPGYQAFY VNSVNSSIPKAC VVLKNYQEMVVEG Q5RHW5 RPREMLVEIQQEYPDDTE AGC NDEMME IPTVTYNIILEKIKRLKPLR Q HIFIPSCVVLTR HQGDIFMSFAEHSE Q5RKN7 KPRRLYIDFKDVGWQDWI HGE PFPLSESLNGTNHAILQTL VPIKLSPISMLYYDNNDNV G IAPQGYLANY VHSFDPKGTPQPC VLREYEDMVVDE Q5YJC3 RRKRMYVDFRLLGWSDW EGE KYPIDNYLRPTNHATVQT TTNELSTISILYTEDGSNN G IIAPQGYDAYL IVNSLDPSIAPKAC VVYKNYKDMVVER Q63434 RPMEKLVYIADEHPNEVS SGC GDEGLH VALKTANTTMQILKIPPNR E HIFSPSCVLLSR DPASYVEMTFSQDVL Q64FZ6 RPIETLVDIFQEYPDEIEYI AGC NDEALE VPTSESNVTMQIMRIKPH E FKPSCVPLMR QSQHIGEMSFLQHSR Q66KL4 KKRRLYIDFKDVGWQNW YGE PYPLTEMLRGTNHAVLQT APTKLSPISMLYYDNNDN G VIAPRGYMANY LVHSVEPESTPLPC VVLRHYEDMVVDE Q68KG0 SKKPLHVNFKDMGWDD EGL EFFLRSHIEPTNHAVIQIL VPTRLSPISILYTDSANNV G WIIAPLEYEAYH MNSMDPETTPPTC VYKQYEDMVVES Q6AYU9 RRHSLYVDFSDVGWNDWT HGD PFPLADHINSTNHAJVQTL VPTELSAISMLYLDHYDK G VAPPGYQAFY VNSVNSSIPKAC VVLKNYQEMVVEG Q6EH35 KRHPLYVDFNDVGWNDW HGE PTPLADFLNTINHAIVQT VPTELSAISMLYLDENEKV G IVAPFGYGAFY LVNSVNSKJPKAC VLKNYQDMVVEG Q6H8S7 RTREMLVDVFQEYPDEIE AGC NDEALE VPTETKNVTMEVIQVKQR E HIYIPSCVVLMR VSQEHFLLSFTEHRK Q6H8S8 RTREMLVDVFQEYPDEIE AGC NDEALE VPTEIKNVTMEVIQVKQR E HIYIPSCVVLMR VSQHHFLLSFTFHRK Q6HA10 SRKPLHVNFKFLGWDDWI EGV DFPLRSHLEPTNHAIIQTL VPTKLTPISILYIDAGNNV G IAPLEYEAYH MNSMDPGSTPTSC VYKQYEDMVVES Q6J384 QRQPLYVDFREVGWDDW QGE PFPLADELNSTNIIAIVQIL VPTELSPISMLYMDEYEK G IVAPPGYNAYF VNSVNASIPRAC VVLKNYQDMVVEG Q6J385 RRHALYVDFREVGWNDW HGE PFPLADHLNSTNHAIVQTL VPTELSPISMLYLDEYGKV G IVAPPGYHAYF VNSVNASIPRAC VLKNYQDMVVEG Q6J386 ARYPLYVDFSDVGWNDW QGE HEPLPQHLNSTNHAIVQTL IPTELTPIALIYLDEYEKV G IVAPPGYNAFF VNSVNPFPRAC VLKNYQDMVVEG Q6J936 QPRETLVSILEEYPGFIAHI GGC TDESLE TATGKESVGREIMRLSPH E IRPSCVTALR KGTSEKEVMQFTEHID Q6KF10 SKKPLEVNFRELGWDDWI EGV DFPLRSIILEPTNHAIIQTL VPTKLTPTSILYIDAGNNV G IAPLEYEAYH MNSMDPGSTPPSC VYKQYEDMVVES Q6P4J4 KKHELYVSFKDLGWQDW EGE AFPLNSYMNATNHAIVQT APTQLNPISVLYFDDSSNV G IIAPEGYAAFY LVHFINPDTVPKPC ILKKYRMMVVRA Q6PAF3 KRHSLYVDFSDVGWNDWI HGD PFPLADGLNSTNHAIVQTL VPTELSAISMLYLDHYDK G VAPPGYQAFY VNSVNASIPKAC VVLKNYQEMVVEG Q6R5A5 RPMPTTVRVSDEYFNDTS GGC NDESLE VPTETSNVTMQLMVTSAH E ERYNPQCVTLMR NGGSNDNGSGGGIGSGMR EMSFLQHNK Q6RF65 RRMSLYVDFSDVGWNDWI HGD PFPLADHLNSTNHAIVQTL VPTELSAISMLYLDHYDK G VAPPGYAFY VNSVN3SIFKAC VVLKNYQEMVVEG Q6TVT2 QPMKTFVKVSDEYFDNT GGC NDESLE VPTETSNVTMQIMTTSAY H NDEHSPPCVTIMR NDGGTSGGTSSGMREMSP LQHNK Q6WZM0 HPIETLVDFQEYPDEIEYI GGC NDEGLE VPTEESNTTMQVGIFGKW L FKPSCVTLMR GKGGIGRGVILWEQVVPGR Q6XDQ0 KRHPLYVDFNDVGWNDW HGE PFPLADHLNSTNHAIVQTL VPTELSAISMLYLDENEKV G IVAPPGYSAFY VNSVNSKIPKAC VLKNYQDMVVEG Q6YLN3 RPIETLVDIFQEYPDEIEYI AGC NDEALE VPTSESNITMQIMRIKPHQ E FKPSCVPLMR SQHIGEMSFLQHSR Q75N54 KRHALYVDFSDVGWNEW HGE PFPLADHLNSTNHAIVQTL VPTDLSPISLLYLDEYEKV G IVAPPGYHAFY VNSVNSNIPRAC ILKNYQDMVVEG Q75RY1 SRRFLHVDKELGWDDWI EGL DFPLRSHLEFINHAHQTL VPARLSPISILYIDAANNVV G IAPLDYEAYH LNSMAPDAAPASC YKQYEDMVVEA Q72WK6 RRHPLYVDFVDVGWNDW HGD PFPLADHLNSTNHAIVQTL VPTALSSISMLYLDEENKV G IVAPPGYDAFY VYSINPNIVPKAC VLKNTQDMAVLG Q772M8 KPRPMVFRVHDEHFELTS GGC NDESLE VFTEEANVTMQLMGASVS D QRFNPPCVTLMR GGNGMQHLSFVEHKK Q7SDH3 RRHALYVDFSDVGWNDW HGE PFPLADHLNSTNHAIVQTL VPTELSAISMLYLDEHDK G IVAPPGYQAYY VNSVNNNIPKAC VVLKNYQEMVVEG Q78DH4 RRHALYVDFSDVGWNDW HGE PFPLADHLNSTNHAIVQTL VPTELSAISMLYLDEHDK G IVAPPGYQAYY VNSVNNNIPKAC VVLKNYQEMVVEG Q72DH5 RRHALYVDFSDVGWNDW HGE PFPLADHLNSTNHAIVQTL VPTELSAISMLYLDEHDK G IVAPPGYQAYY VNSVNNNIPKAC VVLKNYQEMVVEG Q78DH6 RRHALYVDFSDVGWNDW HGE PFPLADHLNSTNHAIVQTL VPTELSAISMLYLDEHDK G IVAPPGYQAYY VNSVNNNIPKAC VVLKNYQEMVVEG Q7Q3Q7 QRKPLYVDFSDVGWNDW QGD RFPIADHLNTTNHAIVQTL VPTQLSSISMLYLNEQNK G IVAPPGYEAYY VNSYNPILAPKAC VVLKNYQDMTVVG Q7T2S8 KKHELYVSFRDLGWQDW DGE SFPLNAHMNATNHAIVQT APTKLNAISVLYFDDSSNV G IIAPEGYAAFY LVHLMFPDNVPKPC ILKKYRNMVVRS Q7Z4P5 SRKPLHVDFKELGWDDWI EGL DFPLRSHLEPINHAIIQTL VTARLSPISILYIDAANNVV G IAPLDYEAYH LNSMAPDAAPASC YKQYEDMVVEA Q80482 KRHALYVDFSDVGWNEW QGE PFPLADHLNSTNHAIVQTL VPTDLSPTSLLYLDEYEKV G IVAPPGYHAFY VNSVNSNITRAC ILKNYQDMVVEG Q80482 KRHALYVDFSDVGWNEW QGE PFPLADHLNSTNHAIVQTL VPTDLSPTSLLYLDEYEKV G IVAPPGYHAFY VNSVNSNITRAC ILKNYQDMVVEG Q811S3 RRHSLYVDFSDVGWNDWI HGD PFPLADHLNSTNHAIVQTL VPTELSAISMLYLDEYDK G VAPPGYQAFY VNSVNSSIPKAC VVLKNYQEMVVEG Q866G4 QPIETLVDIFQFYPDEIEYI GGC NDESLE VPTEEFNVTMQIMRIKPH H FKPSCVPLVR QGQHIGFMSFLQHNK Q869A4 RRHALYVDFSDVGWNDW HGD PFPLFDHLNTNHAIVQTL VFTELSPISMLYKDKFDN G HAPPGYNAYF VNSANPAAVPRAC VVLKNYQDMVVEG Q86RL7 RRHALYVDFQEVGWEDW QGD NFPLAQHLNSTNHAIVQT VPTELSAISMLYLNERQKV G IVAPDGYNAYF LVNSVDPTAVSKAC QLKNYQDMVVEA Q80RW3 KKHELYVSFQDLGWQDW DGE SFPLNAHMNATNHAIVQT APTKLNAISVLYFDDNSNV G IIIAPKGYAANY LVHLMNPFYVPKPC ILKKYRNMVVRA Q8HRW9 SRKALHVNFKDMGWDD EGL EFFLRSHLEPTNHAVIQTL VPTRLSPISILFIDSANNVV G WRAPLEYEAFH MNSMDPESTPPTC YKQYEDMVVES Q8CCE0 KKHELYVSFRDLGWQDW DGE SFPLNHMNATNHAIVQT APTKLNAISVLYFDDSSNV G IIAPEGYAAFY LVHLMFFDHVTKPC ILKKYRNMVVRS Q8HY70 RPIETLVDIFQEYPDEIEYI GGC NDEGLE VPTEEFNITMQIMRIKHQ H FKPSCVPLMR GQHGIGEMSFLQHSK Q8HY75 RPVERLVDIVSEYPSEVEH TGC SDETMH MPLETANVTMQLMKYHS H MFSPSCVSLMR LDQPFFVEMSFSQHVR Q8IAE3 SKHSLYVDFAIVQWDSWI QGE PYPMPEHLNPTNHAIVQTI VPTELDTLNMLYLNEKEQ G LPEGYQAYY VHSADPSSVPKAC IILKNYKDMIVTS Q8IFE2 RRHALYVDFSDVGWNDW HGE PFPLADHLNSTNHAIVQTL VPTELSAISMLYLDEHDK G IVATTGYQAYY VNSVNNNIPKAC VVLKNYQEMVVEG Q8JIJ2 RRHALYVDFSDVGWNDW HGE PFPLADHLNSTNHAIVQTL VPTELSAISMLYLDEHDK G IVAPPGYQAYY VNSVNNNIPKAC VVLKNYQEMVVEG Q8JIJ3 RRHALYVDFSDVGWNDW HGE PFPLADHLNSTNHAIVQTL VPTELSAISMLYLDEHDK G IVAPPGYQAYY VNSVNNNIPKAC VVLKNYQEMVVEG Q8JIJ4 RRHALYVDFSDVGWNDW HGE PFPLADHLNSTNHAIVQTL VPTELSAISMLYLDEHDK G IVAPPGYQAYY VNSVNNNIPKAC VVLKNYQEMVVEG Q8JIJ5 RRHALYVDFSDVGWNDW HGE PFPLADHLNSTNHAIVQTL VPTELSAISMLYLDEHDK G IVAPPGYQAYY VNSVNNNIPKAC VVLKNYQEMVVEG Q8JIJ6 RRHALYVDFSDVGWNDW HGE PFPLADHLNSTNHAIVQTL VPTELSAISMLYLDEHDK G IVAPPGYQAYY VNSVNNNIPKAC VVLKNYQEMVVEG Q8JIJ7 RRHALYVDFSDVGWNDW HGE PFPLADHLNSTNHAIVQTL VPTELSAISMLYLDEHDK G IVAPPGYQAYY VNSVNNNIPKAC VVLKNYQEMVVEG Q8JIJ8 RRHALYVDFSDVGWNDW HGE PFPLADHLNSTNHAIVQTL VPTELSAISMLYLDEHDK G IVAPPGYQAYY VNSVNNNIPKAC VVLKNYQEMVVEG Q8JIJ9 RRHALYVDFSDVGWNDW HGE PFPLADHLNSTNHAIVQTL VPTELSAISMLYLDEHDK G IVAPPGYQAYY VNSVNNNIPKAC VVLKNYQEMVVEG Q8JIK0 RRHALYVDFSDVGWNDW HGE PFPLADHLNSTNHAIVQTL VPTELSAISMLYLDEHDK G IVAPPGYQAYY VNSVNNNIPKAC VVLKNYQEMVVEG Q8JIK1 RRHALYVDFSDVGWNDW HGE PFPLADHLNSTNHAIVQTL PFPLADHLNSTNHAIVQTL G IVAPPGYQAYY VNSVNNNIPKAC VVLKNYQEMVVEG Q8JIK2 RRHALYVDFSDVGWNDW HGE PFPLADHLNSTNHAIVQTL PFPLADHLNSTNHAIVQTL G IVAPPGYQAYY VNSVNNNIPKAC VVLKNYQEMVVEG Q8MJV5 RRHSLYVDFSDVGWNDWI HGD PFPILADHLNSTNHAIVQTL VPTELSAISMLYLDEYDK G VAPPGYQAFY VNSVNSSIPKAC VVLENYQEMVVEG Q8MWG4 KRHVLYVDFGDVGWNDW RGE PFPMGQHLNSTNHAVMQ VPSDLSAISMLYLDHLDKV G IVAPPGYNAYF TLVHSVDPTAVPKAC VLKNYQDMVVEG Q8MXC2 QRHPLYVDFSFVGWNDWI KGE PFPIADHLNTTNHAIVQTL VPTTLEAISMLFMNEHSK G VAPPGYQGFY MNSVNFNNVPPAC VVLKNYQDMVVDG Q8MXZ3 KRKNLFVNFEDLDWQEWI QGE AFPLNGHANATNHAIVQT APTALSPITVLYYDDSRNV G IAPLGYVAFY LVHHMSPSTVPQPC VLKKYENMVVRA Q8SPL5 RPIETLVDFQHYPDFJEYI GGC NDEGLE VPTAEFNITMQIMRIKPHQ H FKPSCVPLMR SQHIGEMSFLQHSK Q8SPZ9 RPIETLVDIFQEYFDEJEYI GGC NDEGLE VPTEEFNITMQIMRIKPHQ H FKPSCVPLMR GQHIGEMSFLQHNK Q8WMQ4 RPIETLVDIFQEYPDEJEYI GGC NDEGLE VPTEFFNIAMQIMRIKPHQ H FKPSCVPLMR GQHIGEMSFLQHNK Q8WS99 RPHPLYVDFTDVGWNSWII QGE PFPLVDHLNATNHAIVQT VPTDLSAISMLYLDDSDSV G VAPAGYQAYY LVNSASPQIAPKAC ILRNYQDMVVEG Q90723 KPRRLYSFSDVGWENWII LGE PFPLTAELNSTNHAILQTM VPVRLSPISILYYDNSDNV G APQGYMANY VHSLDPEGTPQPC VLRHYEDMVVDE Q90751 KRHPLYVDFNDVGWNDW HGE PFPLADHLNSTNHAIVQTL VPTELSAISMLYLDHNEKV G IVAPPGYSAFY VNSVNSKIPKAC VLKNYQDMVVEG Q90752 RRHALYVDFSDVGWNDW HGD PFPLADHLNSTNHAIVQTL VPTELSAISMLYLDHYDK G IVAPPGYQAFY VNSVNSSIPKAC VVLKNYQEMVVEG Q90X23 QPRETLVSILEEYPGEISIHI GGC TDESLE IAIGKRSVGREIMRLSPH H FRPSCVTAIR KGTSEKEVMQFTEHTD Q90X24 QPRETLVSILEEYPGEISIHI GGC TDESLK TATGKRSVGRFIMRVDPH H FRPSCVTAIR KGTSEKEVMQFTFHTD Q90Y81 RRHALYVDFREVGWNDW HGE PFPLADHLNSTNHAVQTL VPTELSFISMLYLDGYGKV G IVAPPGYHAYF VNSVNASIPRAC VIKNYQDMVVEG Q90Y82 ARYPLYVDFSDVGWNDW QGE HFPLPQHLNSTNHAIVQTL IPTELTPIALLYLDFVEKV G IVAPPGYNAFF VNSVNPEVPRAC VLKNYQDMVVEG Q90YD6 RRHSLYVDFSDVGWNDWI HGD PTPLADHLNSTNHAIVQTL VPTDLSAISMLYLDEYDK G VAPPGYQAFY VNSVNSSIPKAC VVIKNYQFMVVEG Q90YD7 RRHPLYVDFSDVGWNDW HGE PFPLADHLNSTNHAIVQTL VPTELSAISMLYLDENEKV G IVAPPGYHAFY VNNVNPNIPKAC VLKNYQDMVVEG Q91403 KKHELYVSFRDLGWQDW EGE AFPLNSYMNATNHAIVQT APTQLNAISVLYFDDSSNV G IIAPEGYAAYY LVHFINPETVPKPC ILKKYRNMVVRA Q91703 RRHSLYVDFSDVGWNDWI HGD PFPLADHLNSTNHAJVQTL VPTELSAISMLYLDHYDK G VAPPGYQAFY VNSVNASIPKAC VVLKNYQEMVVEG Q95LQ4 RPIETLVDIFQEYPDEIEYI GGC NDEGLE VPTEEFNTTMQLMRIKPHQ H FKPSCVPLMR GQHIGEMSFLQHSK Q95NE5 RPIETLVDIFQEYPDEIEYI GGC NDEGLE VPTEEFNTTMQLMRIKPHQ H FKPSCVPLMR GQHIGEMSFLQHSK Q95W38 RRHPLYVDFREVGWDDW HGD PFPLSAHMNSTNHLAVVQT VPTQLTSISMLYLDEESKV G IVAPPGYFAWY LMNSMNPGLVPKAC VLKNYHEMAVVQ Q98P50 KPRLYISFSDVGWEVWU LGE PFPLTAELNSTNHAILQTM VPVRLSPISILYYDNSDNV G APQGYMANY VHSLDPEGTFQPC VLRHYEDMVVDE Q99PS1 HPIEILVDIFQEYPDEIEYI GGC SDEALE VPISESNITMQIMRVKPH H FKPSCVPLMR QSQHIGEMSELQHSR Q9BDP7 HPIETLVDIFQEYPDEIEYI GGC NDEGLE VPTEESNTIMQIMRIKFHQ H FKPSCVPLMR GQHIGEMSFLQHNK Q9BDW8 SRRFLHVDFKELGWDDWI EGV DFPLRSHLEPINHAHQTL VPARLSPISILYIDAANNVV G IAPLDYEAYH LNSMAPDAAPASC YKQYEDMVVEA Q9BDW9 SRRFLHVDFKELGWDDWI EGV DFPLRSHLEPINHAHQTL VPARLSPISILYIDAANNVV G IAPLDYEAYH LNSMAPDAAPASC YKQYEDMVVEA Q9DGN4 SRRFLHVDFKELGWDDWI EGV DFPLRSHLEPINHAHQTL VPSRLSPISILYIDSGNNVV S IAPLDYEAYH LNSMAPDAAPASC YKQYEDMVVES Q9BRL6 HPIETLVDIFQEYPDEIEYI GGC SDEALE VPTSESNTTMQIMRVKPH H FKPSCVPLMR QSQIEGEMSFLQHR Q9GK00 HPIETLVDIFQEYPDEIEYI GGC NDEGLE VPTEEFNIIMQIMRIKFHQ H FKPSCVPLMR GQHIGEMSFLQHNK Q9CKR0 HPIETLVDIFQEYPDEIEYI GGC NDEGLE VPTAEFNTTMQIMIUKPHQ H FKPSCVPLMR SQIIGEMSFLQHSK Q98T6 KKHELYVSFRDLGWQDW EGE APPLNSYMNATNHATVQT AFTQLNAISVLYFDDSSNV G UAPEGYAAYY LVHFINPFTVPKPC ULKKYRNMVVRA Q9MYV3 RPIETLVDIFQHYPDEIHYI GGC NDEGLE VPTEEFNTTMQIMRIKPHQ H PKPSCVPLMR GQHIGEKSFLQHSK Q9MYV3-2 RPIEILVDIFQEYPDEDIEYI GGC NDEGLE VPTEEFNIIMQIMRIRFHQ H FKPSCVPLMR GQHIGEMSFLQHSK Q9MYV3-3 RPIETLVDIFQEYPDEIEYI GGC NDEGLE VPTEEFNTIMQMRIKPHQ H FKPSCVPLMR GQHIGEMSELQHSK Q9MZB1 RRISTLVDIFQHYPDEIEFIF GGC NDESLE VPTEEFNTTMQIMRIKFHQ E KPSCVPLMR SQHIGEMSFLQHNK Q9MZV5 RRHSLYVDFSDVGWNDWI HGD PFPLADHLNSTNHAIVQTL VPTELSAISMLYLDHYDK G VAPPGYQAFY VNSVNESIPKAC VVLKNVQEMVVEG Q9PTF9 KKHELYVSFRDLGWQDW EGE VFPLNSYMNATNHAIVQT APTQLHGISVLYFDDSSNV G Q9QX39 DAPEGYAAYY LVHFINPETVPKPC VPTSESNITMQIMRIKPHQ E HPIETLVDIFQEYPDHIEYI GGC NDEALE SQHIGEMSFLQHNR Q9U418 PKPSCVPLMR VPTDLSPISMLYLNENDQ G RRHSLYVDFSDVGWNDWI HGE PFPLADHLNSTNHAIVQTL VVLENYQDMVVEG Q9U5E8 VAPPGYQAYY VNSVNFLAVPKAC VPTELSPISMLYLDFYDKV G RRRSLYVDFSDVGWNDWI DGE PFPLADHLNSTNHYAIVQTL ILKNYQEMVVEG Q9W8C0 VAPPGYQAYY VHSVKASAVPQAC VPSKISP

SILYIDSGNNVV G SRKPLHVNFKELGWDDWI EGL DFPLRSHLHOTNHATIQTL YKQYEDMVVES Q9W6G0 IAPLDYEAYH MNSMDPESTPPSC VPTRLSPISILFIDSANNVV G SRKALHVNFKDMGWDD EGL EGPLRSHLEPINHAVIQTL YKQYEDMVVES Q9W753 WUAPLEYEAYH KGNSMDFESTPPTC VPTKLTPIS

LYIGADNNV G SKKPLHVNFKELGWDDWI EGV DFPLRSHLEPTNHAJJQTL VYKQYEDMVVES Q9XS47 IAPLEYEAHN MNSMNPGSTPPSG VPLETANVTMQLMKYRS E KPVERLVDIVSEYASEMEH TGC SDES

H LQDEFFEVMSFSQHVR Q9XYQ7 IFSPSCVSLMR GPTELSAISMLYLDHYEKV G RRHTLYVDFSDVHWNDW HGE PFPLAEHLNTTNHAIVQTL VLKNYQDMVVEG Q9XYQ8 IVAPAGYQAYY VNSVNPALVPKAC VPTELSAISMLYLDFYEKV G RRHELYVDFSDVHWNDW RGE PFPLAHHLNJTNHATVQTL VLKNYQDMVVEG Q9XZ69 IVAPAGYQAYY VNSVNPALVFKAC VPTELSAISMLYLDEYEKV G RRHPLYVDFSDVHWNDW HGE PFPLAEHLNTTNHAIVQTL VLKNYQDMVVEG Q9YGH7 IVAPAGYQAYY VNSVNPALVPKAC APTQLNAISVLYFDDSSNV G KKHELYVSFKDLGWQDW EGE AFPLNSYMNATNHAIVQT ILKKYRNMVVRA Q9YGV1 HAOEGYAAFY LVHTNPDTVPKPC APTKLSPISMLYYDNNDN G KKRELYUDFJDVGWQNW HGE PYPLTEMLRGTNHAVLQT VVLRHYEDMVVDE Q9YMF3 VIAPRGYMANY LVHSVEPENTPLFC VPTEEANVTMQLMGASVS D KPRPMVFRVHDEHPELTS GGC NDESLE GGNGMQHLSFVEHKK QRFNTPCVTLMR GUR_GYM3Y VKKDEL IPYYLD EPLE KKVNWWDHK ALO1_ACRLO IKNDSL QPDGSQGN SRY HKEPGWVAGY ALO2_ACRLO IANRNG QPDGSQGN SGY HKEPGWVAGY ALO3_ACRLO IKNGNG QPNGSQGN SGY HKQPGWVAGY CVP3_PIMHY GFPGRR SPTEE EGLV QPRKNGPSM CVP5_PIMHY SSMGAS QIGSAT GV NVHTLR Q2MJU0_LYSTE SPPGFF QTDDD FTKLFR LETVGR Q2PQC7_BEMTA ISNWTK KPDGSJGN SGY FQFKFDWEYGI Q2PQC8_BEMTA LTKGAS KGDGSMGN SGF WQANPSSPGS Q2PQC9_BEMTA LSDGAA QSDGSIGN SGF LQYVEPGGTATPGT Q2PQD0_BEMTA LPDGAP QADGSMGN TTF LQHEQPGGTPGH Q3LTD6_9DRT IFDGGR HESDPGPG SGF YRERNWKDGD FSPM_SOLLC NEP SSNSD IGITL QF KEKIDQYG

YRT MCPI_SOLLC HKP STQDD SGGIF QA WRTAGT MCPI_SOLTU NKP KTHDD SGAWF QA WNSSART O24372_SOLTU NDY NTNAD LGITL PW KLKKSSSGFTYSE O24373_SOLTU NDY TINAD FGITL PW KLSKSPSGGTYSE O24639_SOLTU NDY TINAD FGITF PW KLKKSPSGFTYSE Q38480_SOLTU NDY TTNSD FGITL PW KLKKSPGGGTYSE Q38486_SOLTU NDY NTNAD FGITL PW KLKKSSSGFTYSE Q41432_SOLTU NDY NTNAD FGITL PW KLKKSSSGFTYSE Q948ZS_SOLTU NDY TTNAD FGITL PW KLKKSPSGGTYSE Q949A1_SOLBR NYY TSNAD IGITF QW KVKTNPDGSASRT Q9SEH8_SOLTU NKP KTHDD SGAWF QA WNSART Q9SXP0_HYONI FKY NVESD SDGWL YN VPSAFSGWRSQ POI_MUSDO LANGSK YSHDV TKR HNYAKK Q170Q5_AEDAE AANGEY LTHSE SGS LSFSYK Q170Q6_AEDAE AANGEY LTHSE SGS LSFSYK Q5BN34_ANOGA AKNNEY LTHRD SGS LSFSYK AMP1_MESCR IKNGKG REDQGPPF SGF YRQVGWARGY AMP1_MIRIA IGNGGR NENVGPPY SGF LRQFGQGYGV AMP2_MIRIA IGNGGR NEMVGPPY SGF LRQFNQGYGV PAFP_PHYAM IKNGGR NASAGPPY SSY FQLAGQSYGV Q54A12_PHYAM IKNGGR NASAGPPY SSY FQLAGQSYGV Q9SDS1_PHYAM IKNGGR VASGGPPY SNY IQIAGQSYGV DEF1_PETHY PTWDSV INKKP VA CKKAKFSDGH SKILRR DEF2_PETHY PTWEGI INKAP VK CKAQPEKFTDGH SKILRR ALB1A_PEA NGV SPFEMPP GTSA R IPVGLVVGY ALB1B_PEA NGV SPFEMPP GSSA R IPVGLVVGY ALB1C_PEA NGV SPFDJPP GSPL R IPAGLVIGN ALB1D_PEA NGV SPFEMPP GTSA R IPVGLFIGY ALB1E_PEA NGV SPFEMPP GSSA R IPVGLLIGY ALB1F_PEA NGV SPFEMPP GTSA R IPVGLVIGY ALB1_GLYSO NGA SPFEVPP RSED R VPIGLFVGF ALB1_PHAAN NGA SPEQMPP GSTD L IPAGL

FVGY ALB1_PHAAU NGA SPFEMPP RSTD R IPIALFGGF ALB2_SOYBN NGA SPFEVPF RSRD R VPIGLFVGF O24095_MEDTR PTAGTA SQRRGNS GGIE I VSQGYPYDGGI O24100_MEDTR ARVGMR SRALPNP GDIVT R VHLHLVGST O48617_MEDTR PFAGRV SQYFSNA GDSEE I VSEWSHYDGGI Q6A1C7_9FABA NGV SPFEMPP GSSD R IPVGLVVGY Q6A1C8_TRIFG SGI SPFEMPP RSSD R IPIVLVGGY Q6A1C9_ONOVI DGV SPFEMPP GSTD R VTWGLFVGQ Q6A1D1_9FABA NGRDW SPFEMPP GDAQN R IPVVLVGGY Q6A1D2_MELAB SGI SSFEMPP RSSS R IPVVLLGGN Q6A1D3_LONCA NGRDV SPFEMPP DDAIN R IPWGLVVGQ Q6A1D4_CANBR SGG SPFEMPP GSSD R IPWGLVAGY Q6A1D5_9FABA SGA FPFQMPP GSTD R VPWGLFVGQ Q6A1D6_9FABA SGA SPFERPL GSTD R IPIVLLAGF Q6A1D7_9FABA SGV SPFEMPP GSTD R IPWGLFVGE Q7XZC2_PHAVU SGV SPFERPP GSTRD R IPYGLFIGA Q7XZC3_SOYBN NGA SPFEMPP RSRD R VPIGLVAGF Q7XZC3_MEDTR SGA SPFEMPP RSSD R IPIGLVAGY SOCT_MESMA GP FITDANMARK RE CGGIGK IGPQ SOCX_MESMA GT FTTDANMARK RE CGGNGK IGPQ SCTT_MESTA GP FTTDPQTQAK SE CGRKGGV KGPQ SCX1_BUTEU MP FTTRFDMAQQ RA CKGRGK PGPQ SCX1_BUTSI KP FTTDPQMSKK AD CGGKGKGK YGPQ SCX1_LEIQH GP FTTDHQMEQK AE CGGIGK YGPQ SCX3_BUTEU MP FTTDHQQTARR RD CGGRGRK FGQ SCX3_MESTA PP FTTNPNMEAD RK CGGRGY ASYQ SCX4_BUTEU MP FITDHNMAKK RD CGGNGK FGPQ SCX5_BUTEU MP FITDPNMAKK RD CGGNGK FGPQ SCX8_LEIQH SP FTTDQQMTKK YD CGGKGKGK YGPQ SCXL_BUTSI GP FTKDPETEKK AT CGGYGR FGPQ SCXL_LEIQU MP FTTDHQMARK DD CGGKGRGE YGPQ SCXT_ANDMA GP FTTDFYTESK AT CGGRGK VGPQ SCX8_BUTEU MP FTTDPNMANK RD CGGGKK FGPQ IPIXA_PANIM LPHLKR KADND GKK KRRGINAEKR SCX1_OPICA LPHLKR KHNND SKK KRRGINPHKR SCX2_OPICA LPHLKR KHNND SKK KRGANPEKR SCXC1_MESMA NRLNKK NSDGD RYGFR ISTGVNYY SCXC_SCOMA LPHLKL KSNKD SKK KRHGTNIEKR KGX11_CENNO VDKSR AKYGYYQE QD CKNAGHNGGT MFFK KGX12_CENEL VDKSR AKYGYYQE TD CKKYGHNGGT MFFK KGX13_CENGR VDKSR AKYGHYQE TD CKKYGHNGGT MFFK KGX14_CENSC VDKSR AKYGYYQE QD CKKAGHNGGT MFFK KGX15_CENLL VDKSR SKYGYYQE QD CKKAGHNGGT MFFK KGX16_CENEX VDKSR AKYGYYQE QD CKKAGHSGGT MFFK KGX31_CENNO VNKSR AKYGYYSQ FV CKKAGHKGGT DFFK KGX32_CENEL VDKSR AKYGYYQQ EI CKKAGHRGGT HFFK KGX33_CENSC VDKSR AKYGYYGQ EV CKKAGHRGGT DFFK KGX34_CENGR VDKSR QKYGNYAQ TA CKKAGHNKGT DFFK KGX41_CENLL VDKSK SKYGYYGQ DS CKKAGDRAGN VYFK KGX42_CENNO VDKSK GKYGYYQE QD CKNAGHNGGT VYYK KGX43_CENEX VDKSK GKYGYYGQ DE CKKAGDRAGT EYYK KGX44_CENEX VDKSK AKYGYYYQ DE CKKAGDRAGT EYFK KGX45_CENEX VDKSQ AKYGYYYQ DE CKKAGDRAGT EYFK KGX46_CENLL VDKSK SKYGYYGQ DK CKKAGDRAGN VYEK KGX47_CENLL VDKSK AKYGYYGQ DE CKKAGDRAGN VYLK KGX48_CENEL VDKSK GKYGYYEQ DE CKKAGDRAGN VYYK KGX49_CENSC VDKSR GKYGYYGQ DD CKKAGDRAGT VYYK KGX4A_CENSC VDKSR GKYGYYGQ DE CKKAGDRAGT VYYK KGX4B_CENNO VDKSQ GKYGYYGQ DE CKKAGERVGT VYYK KGX4C_CENSC VFKSK GKYGYYGQ DE CKKAGDRAGT VYYK KGX4D_CENNO VDKSK GKYGYYGQ DE CKKAGDRAGT VYYK KGX52_CENSC VDKSR AKYGYYGQ EV CKKAGJNGGT MFFK KGX52_CENGR VDKSR QKYGFYGQ TD CKKAGJTGGT IYEK A6N2U8_MOMCH PRIWME KRDSD MAQ I VDGH ISLI_MOMCH PRIWME KRDSD LAQ I VDGH ITH_LAGCE PRIYME KHDSD LAD V LEHGI ITR1_CITLA PRIYME KRDAD LAD V LQHGI ITR1_CUCMA PRILME KKDSD LAE V LEHGY ITR1_LUFCY PRILME SSDSD LAE I LEQGF ITR1_MOMCH PRILKQ KRDSD PGE I MAHGF ITR1_MOMCO PRILQR RRDSD PGA I RGNGY ITR1_MOMRE PRILME KRDSD LAQ V KRQGY ITR1_TRIKJ PRILMP KVNDD LRG K LSNGY ITR2B_CUCSA PRILMK KHDSD LLD V LEDIGY ITR2_ERYDI PRILMR KRDSD LAG V QKNGY ITR2_ECBEL PRILMR KQDSD LAG V GPNGF ITR2_LUFCY PRILMS SSDSD LAF I LFQDGF ITR2_MOMCH PRIWME KRDSD MAQ I VDGN ITR2_MOMCO PRILKK KRDSD PGA I RGNGY ITR2_SECED PKILMR KRDSD LAK T QESGY ITR3_CUCMC PKILMK KQDSD LLD V LKEGF ITR3_CUCPE PKILME KKDSD LAE I LEHGY ITR3_CYCPE PRILME KADSD LAQ I EESGF ITR3_LUFCY PRILME SSDDS LAE I LENGF ITR3_MOMCH PRILKQ KQDSD PGE I MAHOF ITR3_MOMCO PRILKK RRDSD PGE I KENGY ITR4_CUCMA PRILMK KKDSD LAE V LEHGY ITR4_CUCSA PRILMK KHDSD LPG V LEHIEY ITR4_CYCPE PRILME KADSD LAQ I QENGF ITR4_LUFCY PRILMP SSDSD LAE I LENGF ITR5_CYCPE PRILME KADSD LAQ I QESGF ITR5_LUFCY PRILMP KTDDD MLD R LSNGY ITR5_SECED PRILMK KLDTD FPT T RPSGF ITR6_CYCPE PRILMK KKDSD LAE I EEHGF ITR7_CYCPE PRILMK KKDSD LAE I QFHGP ITRA_MOMCH PRIWME TRDSD MAK I VAGH Q9S8D2_CUCME PRILMK KTDRD LTG T KRNGY Q9S8W2_CUCME PRILMK KQDSD LLD V LKEGF Q9S8W3_CUCME PRILMK KQDSD LLD V LKEGF ITR1_MIRIA AKTDQI PPNAPNY SGS VPHPRLRIFV ITR1_SPIOL SPSGAI SGFGPPEQ SGA VPHPILRIFV ITR2_SPIOL SPSGAI SGFGPPEQ SGA VPHPILRIFV ITR3_SPIOL SPSGAI SGFGPPEQ SGA VPHPILRIFV 29C0_ANCSP TKGAD AEDE LDNLFFRRPY EMRYGAGKR A5A3H0_ATRRO IPSGQP PYNEH SGS TYKENENGNTVQR A5A3H1_ATRRO TPTGQP PYNES SGS QEQLNENGHTVKR A5A3H3_ATRRO IPSGQP PYNEN SQS TFKENENGNTVKR A5A3H4_ATRRO IPSGQP PYNEN SKS TYKENENGNTVQR A5A3H5_ATRRO IPSGQP PYNEN SQS TFKENETGNTVKR A9XDF9_GEOA2 ITWRNS MHNDKG FPWS VCWSQTVSRNSSRKEKKCQ A9XDG0_GEOA2 ITWRNS MHNDKG FPWS VCWSQTVSRNSSRKEKKCQ A9XDG1_GEOA2 ITWRNS MHNDKG FPWS VCWSQTVSRNSSGKEKKCQ A9XDG2_GEOA2 ITWRNS MHNDKG FPWS VCWSQTVPRNSSRKEKKCQ A9XDG3_GEOA2 ITWRNS MHNDKG FPWT VCWSQTVSRNSSRKEKKCQ A9XDG4_GEOA2 ITWRNS MHNDKG FPWS VCWSQTVSRNSSRKEKKCQ A9XDG5_GEOA2 ITWRNS VHNDKG FPWS VCWSQTVSRNSSRKEKKCQ AF1_GRARO QKWLWT DSERK EDMV RLW AF2_GRARO QKWMWT DEERE EGLV RLW B1P1A0_CHIJI KKMFGG TVHSD AHLG KPTLKY B1P1A1_CHIJI GGFWWK GRGKPP KGYA SKTWGW B1P1A2_CHIJI RWMFGG TTDSD EHLG RWESPSW B1P1A3_CHIJI GGLMAG DGKSTF SGYN SPTWLW B1P1A4_CHIJI GGLMAG DGKSTF SGYN SPTWKW B1P1B0_CHIJI IEEGKW PKKAP GRLE KGPSPKQKK B1P1B1_CHIJI IEEGKW PKKAP GRLE KGPSPKQKK B1P1B2_CHIJI IEEGKW PKKAP GRLE KGPSPKQKK B1P1B3_CHIJI FKEGHS PKTAP RPLV KGPSPNTKK B1P1B4_CHIJI EPSGKP RPLMRIP GS VEGK B1P1B5_CHIJI QKWMWT DSERK EGYV ELW B1P1B6_CHIJI QKWMWT DSERK EGYV ELW B1P1B7_CHIJI GQFWWK GEGKPP ANFA KIGLYL B1P1B8_CHIJI GQFWWK GEGKPP ANFA KIGLYL B1P1B9_CHIJI GTMWSP STEKP DNFS QPAIKW B1P1C0_CHIJI QKFFWT HPGQPP SGLA TWPIEI B1P1C1_CHIJI QKFFWT HPGQPP SGLA TWPTEI B1P1C2_CHIJI GGLMAG GGKSTF SGYN SPTWKW B1P1C3_CHIJI GGLMDG DGKSTF SGYN SPTWKW B1P1C4_CHIJI GGLMDG DGKSTF SGFN SPTWKW B1P1C6_CHIJI GGLMDG DGKSTF SGFN SPTWKW B1P1C8_CHIJI GEFMWK GAGKPT SGYD SPTWKW B1P1C9_CHIJI GEFMWK GAGKPT SGYD SPTWKW B1P1D0_CHIJI GEFMWK GAGKPT SGYD SPTWKW B1P1D1_CHIJI KGFQVK KKDSE SSYV GSQWKW B1P1D2_CHIJI KGFQVK KKDSE SSYV GSQWKW B1P1D3_CHIJI KGFQVK KKDSE SSYV GRQWKW B1P1D4_CHIJI YDIGEL SSDKP SGYY SPRWGW B1P1D5_CHIJI GGFWWK GSGKPA PKYV SPKWGL B1P1D6_CHIJI GGFWWK GSGKPA PKYV SPKWGL B1P1D7_CHIJI RKMFGG SKHED AHLA KRTFNY B1P1D8_CHIJI RKMFGG SKHED AHLA KRTFNY B1P1D9_CHIJI RKMFGG SVDSD AHLG KPTLKY B1P1E0_CHIJI RKMFGG SVDSD AHLG KPTLKY B1P1E1_CHIJI RKMFGG SVDSD AHLG KPTLKY B1P1E2_CHIJI RKMFGG SVDSD AHLG KPTLKY B1P1E3_CHIJI RKMFGG SVDSD AHLG KPTLKY B1P1E4_CHIJI RKMFGG SVDSD AHLG KPTLKY B1P1E5_CHIJI GGWMAK ADSDD ETFH TRFNV B1P1E6_CHIJI GGWMAK ADSDD ETFH TRFNV B1P1E7_CHIJI GGWMAK ADSDD ETFH TRFNV B1P1E8_CHIJI GGWMAK ADSDD EAFH TRFNV B1P1F0_CHIJI RGYGLP TPEKND QRLY SQHRL B1P1F1_CHIJI LGMFSS NPDNDK EGRK DRRDQW B1P1F2_CHIJI LGLFSS NPDNDK EGRK NRRDKW B1P1F3_CHIJI TKFLGG SEDSE PHLG KDVLYY B1P1F4_CHIJI TKFLGG SEDSE PHLG KDVLYY B1P1F5_CHIJI TKFLGG TKDSF PHLG RKKWPYH B1P1F6_CHIJI RYLMGG SKDGD EHLV RTKWPYH B1P1F7_CHIJI REWLGG SKDAD AHLE RKKWPYH B1P1F8_CHIJI RALYGG TKDED KHLA RRTLPTY B1P1F9_CHIJI RALYGG TKDED KHLA RRTLPTY B1P1G0_CHIJI RWLFGG EKDSD EHLG RRAKPSW B1P1G2_CHIJI RWLFGG EKDSD EHLG RRAKPSW B1P1G3_CHIJI RWLFGG EKDSD EHLG RRAKPSW B1P1G4_CHIJI RWLFGG EKDSD EHLG RRAKPSW B1P1G5_CHIJI RWLFGG EKDSD EHLG RRTKPSW B1P1G6_CHIJI RWMFGG TIDSD EHLG RWEKPSW B1P1G7_CHIJI RWMFGG TIDSD EHLG RWEKPSW B1P1G8_CHIJI KWYLFD KAHED EHLR HSRWDW B1P1G9_CHIJI GEKNDR KTNQD SGFR TKFRR B1P1H0_CHIJI GEKNDR KTNQD SGFR TKFRR B1P1H1_CHIJI RKMFGG SVDSD AHLG KPTLKY B1P1H2_CHIJI LGLFWI NYMDDK PGYK ERSSPW B1P1H3_CHIJI IERMQT EVEAGLP SGAP ICPYIGDCI B1P1H4_CHIJI IERMQT EVEAGLP SGAP ICPYIGDCI B1P1H5_CHIJI IERMQT GVEAGLP SGAP ICPYIGDCI B1P1H6_CHIJI WGANVP EDENSP SPLK EKTFGYGWWYGSPF B1P1H7_CHIJI WGANVP EDENSP PPLK EKTFGYGWWYGSPF B1P1H8_CHIJI GHLHDP PNDRPGHRT IGLQ RYGS B1P1H9_CHIJI RWFWGA KSDSD RYLG KRKWPNI B1P1I0_CHIJI SRKTWP ETSED DKNCSDTFWT QLGYGCSRV CALA_CALS5 ISARYP SNSKD SGN GTFWTCYIRKDPCSKE CALB_CALS5 ISARYP SNSKD SGN GTFWTCFIRKDPCSKE CALC_CALS5 ISARYP SNSKD SGS GIFWTCYLRKDPCSKE F256_OLIOR TYPGQQ KSDDE HGT KTAFIGIU JZT11_CHIJI RKMFGG SVDSD AHLG KPTLKY JZT12_CHIJI QKWMWT DSERK EGYV ELW JZTX1_CHIJI GQFWWK GEGKPP ANFA KIGLYL JZTX3_CHIJI GGFWWK GEGKPP KGYA SKTWGW JZTX5_CHIJI QKWMWT DSKRA EGLR KLW JZTX7_CHIJI GGLMAG DGKSTF SGYN SPTWKW MTX2_GRARO QKWMWT DEERK EGLV RLW MTX4_GRARO LEFWWK NPNDDK RPKLK SKLFKL Q5Y4U5_AGEOR AEKGIR HNIH SGLT KCKGSSCV Q5Y4U6_AGEOR VGENGH RSWYND DGYY SCMQPPNCI Q5Y4U7_AGEOR VGENGR RDWYND DGYY SCRQPPYCI Q5Y4U8_AGEOR VGENQQ ADWAGLH SGYY TCRYFPKCI Q5Y4U9_AGEOR VGENQQ ADWARPH SGYY TCRYFPKCI Q5Y4V0_AGEOR VGENQQ ANWAGPH SGYY TCRYFPKCI Q5Y4V1_AGEOR VGESQQ ADWSGPY KGYY TCQYFPKCI Q5Y4V2_AGEOR VGESQQ ADWSGPY KGYY TCRYFPKCI Q5Y4V3_AGEOR VGESQQ ADWSGPY KGYY TCRYFPKCI Q5Y4V4_AGEOR VGENQQ ADWAGPH SGYY TCRYFPKCI Q5Y4V5_AGEOR VGDGQR ADWAGPY SGYY SCRSMPYCR Q5Y4V6_AGEOR VGENQQ ADWAGPH SGYY TCRYFPKCI Q5Y4V7_AGEOR VGDGQR ADWAGPY SGYY SCRSMPYCR Q5Y4V8_AGEOR AAKNKR ADWAGPW EGLY SCRSYPGCM Q5Y4W0_AGEOR THGS ENGET DGWR RYTGRAVPFM Q5Y4W1_AGEOR VGENQQ ADWAGPH SGLR KELSIWDSR Q5Y4W2_AGEOR LPRNKF NPSSGPR SGLT KELNIWANK Q5Y4W3_AGEOR LPRNKF NPSSGPR SGLT KELNIWDSR Q5Y4W4_AGEOR LPRNKF NPSSGPR SGLT KELNIWASK Q5Y4W5_AGEOR LPRNKF NPSSGPR SGLT KELNIWASK Q5Y4W6_AGEOR LPRNKF NALSGPR SGLT KELNIWASK Q5Y4W7_AGEOR LPRNKF NALSGPR SGLK KELTIWNIK Q5Y4W8_AGEOR LPRNKF NALTGPR SRLR KELSIWDSI Q5Y4X0_AGEOR LPRNKF NALSGPR SGLK KELSIWDSI Q5Y4X1_AGEOR LPRNKF NALSGPR TGLK KELSIWDSR Q5Y4X2_AGEOR LPRNKF NALSGPR SGLR KELSIRDSR Q5Y4X3_AGEOR LPHNRF NALSGPR SGLK KELSIWDST Q5Y4X4_AGEOR LPHNRF NALSGPR SGLR KELSIWDSR Q5Y4X6_AGEOR LPHNRF NALSGPR SGLR KELSIWDST Q5Y4Y0_AGEOR LPHNRF NALSGPR SGLK KELSIWDSR Q5Y4Y1_AGEOR LPRNRF NALSGPR SGLR KELSIWASK Q5Y4Y2_AGEOR LPHNRF NALSGPR SGLK KELSIYDSR Q5Y4Y4_AGEOR LPHNRF NALSGPR SGLR KELSIWDSR SFI1_SEGFL MTDGTV YIHNHND GSCL SNGPIARPWEMVGNCM SFI2_SEGFL MADEIV YIHNHNN GSCL LNGPYARPWEMLVGNCK SFI3_SEGFL MVDGTV YIHNHND GSCL LNGPIARPWEMMVGNCK SFI4_SEGFL MVDGTV YIHNHND GSCL LNGPIARPWEMMVGNCK SFI5_SEGFL MVDGTV YIHNHND GSCL PNGPLARFWEMLVGNCK SFI6_SEGFL MIDETV YIHNHND GSCL LNGPIARPWEMMVGNCK SFI7_SEGFL MADGTV YIHNHND GSCL PNGPLARFWEMLVGNCK SFI8_SEGFL MADGTV YIHNHND GSCL PNGPLARFWEMLVGNCK T244_PHONI RFNGQQ TSDGQ YGK RTAFLRMI TACHC_TACTR ATYGQK KTWSPPN WNLR KAFR TJT1A_HADFO TGADRP AACCP PGTS KGPEPNOVSY TJT1A_HADVE TGADRP AACCP PGTS QGPESNGVVY TJT1B_HADVE TGAGRP AACCP PGTS QGPEPNGVSY TJT1C_HADVE TGADRP AACCP PGTS KAESNGVSY TOG4A_AGEAP IAKDYGR KWGGTP RGRG ICSIMGTNCE TOG4B_AGEAP IAEDYGK TWGGTK RGEP RCSMIGTNCE TONGA_MISBR TPSGQP QPNTQP NNAEEEQTIN NGNTVYR TOT1A_ATRRG IPSGQP PYNEH SGS TYKENENGNTVQR TOT1A_HADIN TFIDQP PYHES SGS TYKANENGNQVKR TOT1A_HADVE IPSGQP PYNEH SOS TFKENENGNTVKR TOT1B_HADFO IRSGQP PYNEH SQS TFKTNFNGNTVKR TOT1B_HADIN IPTTGQP PYNEH SQS TYKANENGNQVKR TOT1B_HADVE IPSGQP PYNEH SQS TYKENENGNTVKR TOT1C_HADIN IRTDQP PYHES SGS TYKANENQVKR TOT1C_HADVE IPSGQP PYNEH SQS TFKENENGNTVKR TOT1D_HADVE IPSGQP PYNEH SKS TYKENENGNTVQR TOT1E_HADVE IPSGQP PYNEH SQS TYKENENGNTVQR TOT1F_HADVE IPSGQP PYSKY SGS TYKTNENGNSVQR TOT2A_ATRIL VLSRV SPDAN GLTPI KMGL TOT2A_HADIN VVNTLG SSDKD GMTPS TLGI TOT2A_HADVE LFGNGR SSNRD ELTPV KRGS TOT2B_ATRIL VLSRV SSDAN GLTPT KMGL TOT2B_HADIN VLNTLG SSDKD GMTPS TLGI TX13_CUPSA TLRNHD TDDRHS RSKMSKDV TCFYPSQAKRELCT TX13_PHONI RSNGQQ TSDGQ YGK MTAFMGKI TX17_PHORI RFNGQQ TSDGQ NGR INAFQGRI TX19_PHOKE ADAWKS DNLP VVNGYSRT MCSANRCN TX1A_GEOA2 ITWRNS MHNDEG FPWS VCWSQTVSRNSSRKEKKCQ TX1_CERCR LGWFKS DPKNDK KNYT SRRDRW TX1_GRARO QKWMWT DSKRK FDMV QLW TX1_HETMC RYLFGG SSTSD KHLS RSDWKY TX1_PSACA KWFMGG DSTLD KHLS KMGLYY TX1_SCOGR RYLFGG KTTAD KHLA RSDGKY TX1_STRCF TRMFGA RRDSD PHLG KPTSKY TX1_THEBL LGMFES SPNNDK PNRE NRKHKW TX21_PHOKE KYNGEQ TSDGQ NGR RIAFMGKI TX22_PHOKE IGHRRS KEDRNG KLYT NCWYPTFDDQWCK TX22_PHONI PKILKQ KSDED RGWK FGFSIKDKM TX24_PHONI RFNGQQ TSDGQ YGK RTAFMGKI TX27_PHONI APRFSL NSDKE KGLR KSRIANMWPTF TX27_PHORI ATRGLL FRDKE KGLT KGRFVNTWPTF TX29_PHONI IFFKP KSDFN KKFK KTTGIVKL TX2_CERCR LGWFKS DPKNDK KNYT SRRDRW TX2_HETMC RYFWGE NDEMV EHLV KEKWPIIYEI TX2_PSACA RWFLGG KSTSD EHLS KMGLDY TX2_THEBL LGMFSS DPKNDK PNRV RSEDQW TX31_PHONI AAVYER GKGYKR EERF KCNIVMDNCT TX325_SEGFL IESGKS THSRSMKNGL PKSR NCRQIQHRHDYLGKRKYS CR TX32_PHOKE APRGQL FSDKL IGLR KSRVANMWPIF TX32_PHONI AGLYKK GKGASP EDRP KCDLAMGNCI TX33A_PHONI ADAYKS NHPRT DGYNGYKRA ICSGSNCK TX35A_PHONI IGHRRS KEDRNG PLYT NCWYPTFGDQWCK TX35_PHONI IGRNES KFDRHG WPWS SCWNKEGQFESDVWCE TX37_PHORI AGLYKK GKGVNT ENRP KCDLAMGNCI TX3A_PHONI ADVYKE WYPEKP KDRA QCILGMTCK TX3_CERCR RKLLGE TIDDD PHLG NKKTWH TX3_LOXIN IKYGDR GSPHGLPSN NDWKYKGRCGCTMGV TCGPNCPSRG TX3_PARSR LGFLWK NPSNDK RPNLV SRKDKW TX3_PSACA RWYLGG KEDSE EHLQ HSTWEW TX3_THEBL LGMGFSS DPNNDK PNRV RVRDQW TX432_HYSGI RYMFGG SVNDD PRLG HSLFSY TX5A_HETVE GWTMDD TSDSD PNWV SKTGFVKNI TX5B_HETVE GWLFHS ESNAD ENWA ATTGRFRYL TXAG_AGEOP LPHNRF NALSGFR SGLK KELSIWDSR TXAG_AGEOR LPHNRF NALSGFR SGLK KELSIWDSR TXC1_CUPSA IPKHEE TNDKHN RKGLFKIK QCSTFDDESGQPTERCA TXC1_HOLCU VGFYGR RSAYED DGVY NCSQPPYCL TXC2_HOLCU VGDGQR ADWAGPY SGYY SCRSMPYCR TXC3_HOLCU VGDGQK ADWFGPY SGYY SCRSMPYCR TXC5_PHONI AQKGIK HDIH TNLK VREGSNRV TXC5_PHORI ADAYKS DSLK NNRT MCSMJGTNCT TXC9_CUPSA IPKHHE TNDKKN KKGLTKMK KCFTVADAKGATSERCA TXDP1_PARLU LGEGEK ADWSGPS DOFY SCRSMPYCR TXDP2_PARLU VGDGQR ASWSGPY DOYY SCRSMPYCR TXDP3_PARLU LNEGDW ADWSGPS GEMW SCPGFGKCR TXDP4_PARLU ATKNQR ASWAGPY DGFY SCRSYPGCM TXDT1_HADVE AKKRNW GKIED CPMK VYAWYNEQGS TXFK1_PSACA GILHDN VYVPSQNP RGLQ RYGK TXFK2_PSACA IPAGKT VRGPMRVP GS SQNK TXFU5_OLIOR VPVYKE WYPQKP EDRV QCSFGMTNCK TXG1D_PLEGU GGFWWK GSGKPA PKYV SPKWGL TXG1E_PLEGU GGFWWK GSGKPA PKYV SPKWGL TXG2_PLEGU RKMFGG SVDSD AHLG KPTLKY TXH10_ORNHU LPPGKP YGATQKIP GV SHNK TXH1_ORNHU KGVFDA TPGKNE PNRV SDKHKW TXH3_ORNHU AGYMRE KEKL SGYV SSRWKW TXH4_ORNHU LEIFKA NPSNDQ KSSKLV SEKTRW TXH5_ORNHU RWYLGG SQDGD RHLQ HSNYEW TXH9_ORNHU APEGGP VAGIG AGLR SGAKLGLAGS TXHA1_SELHA KGFGKS VTGKNE SGYA NSRDKW TXHA3_SELHA KGFGDS TPGKNE PNYA SSKHKW TXHA4_SELHA LGFGKG NPSNDQ KSSNLV SRKHRW TXHA5_SELHA LGFGKG NPSNDQ KSANLV SRKHRW TXHN1_GRARG RYLFGG KTTSD KHLG KFRDKY TXHN2_GRARG RYLFGG KTTAD KHLG KFRDKY TXHP1_HETVE GTTWHY GIDQSE EGWK SRQL TXHP2_HETVE GKLFSG DTNAD EGYV RLW TXHP3_HETVE GTLFSG STHAD FGGI XLW TXJ11_DIGCA MKYKSGD RGKT DQQYLWYKWRNLA RCFTVEVFKKDCW TXI92_DIGCA KKYDVE DSGE QKQYYLWYKWRPLD RCLKSGFFSSKCV TXI1_HETVE GILFSG DTSKD BGYV HLW TXL1_ORNHU LGDK DYNNG SGYV SRTWKW TXLT4_LASPA GGVDAP DKFRFD SYAF LRPSGYGWWHGTYY TXM10_MACGS LAEYQK EGSTVP PGLS SAGRFRKTKL TXM11_MACGS KLTFWR KKDKE GWNI TGL TXM31_OLIOR VPVYKE WYTQKP EDRV Q TXMG1_AGEAP VPENGH RDWYDE EGFY SCEQPPKCI TXMG1_MACGS MGYDIH TDRLF FGLE VKISGYWWYKKYT TXMG2_AGEAP ATKNKR ADWAGPW DGLY SCRSYPGCM TXMG2_MACGS MGYDIE NENLP KHRKLE VETSGYWWYKRKY TXMG3_AGEAP VGDGQR ADWAGPY SGYY SCRSMPYCR TXMG4_AGEAP VGENQQ ADWAGPH DGYY TCRYFPKCI TXMG5_AGEAP VGENEQ ADWAGPH DGYY TCRYFPKCI TXMG5_MACOS KLTFWK KNKKE GWNA ALGI TXMG6_AGEAP VGESQQ ADWAGPH DGYY TCRYFPKCI TXMG6_MACGS VDGS DPYSSDAPR GSQI QCIFFVPCY TXMG7_MACGS APEGGP VVGIG KGYS APGGLLGLVGH TXMG8_MACGS KGLFRQ KKSSE KGSS ESDLDGL TXMG9_MACGS GTNGKP VNGQ GALR VVTYHYADGV TXP1_PARSR QKWMWT DSARK EGLV RLW TXP1_PSACA IPKWKG VNREOD EGLE WKERRSFEV TXP2_PARSR QKWMWT DEERK EGLV RIW TXP3_APTSC NSKGTP TNADE GGK AYNVWNCIGGGCSKT TXP3_BRASM VDFQTK KKDSD GKLE SSRWKW TXP7_APTSC ARVEEA GPWEWP SGLK DGSE TXPR1_THRPR RYWLGG SAGQT KHLV SFRHGW TXPR2_THRPR QKWMWT DSERK EGMV RLW TXPT6_MACGS MGYDIE NSRLH ADLE VKTSGRWWYKKTY TXR3_MACRV KLTFWK KNKEE GWNA ALGI TXU2_HETVE GGLFSG DSNAD EGYV RLW TXVL2_CORVA SEAGEN YKSGR DGLY KAYVVT VSTX1_GRARO GRFMWK KNSND KDLV SSRWKW VSTX2_GRARO QKWMWT DEERK EGLV RLW VSTX3_GRARO LGWFGK DPDNDK EGYK NRRDKW WGRTX_GRARO VRFWGK SQTSD PHLA KSKWPRNI ASTAE_ASTEM GLFGDL TLDGTLA IALELE IPLNDFVGI AX6A_TERSU PEY PHGNE EHHE RYDPWSRELK A2Q0G4_9VIRU TFNYAD MDLQFNKP RQQQLEVGQUPEDFV FRFGKGI A2Q0I8_9VIRU IPNYAH TFIGRTEP RQQELRIGQTIPRDFI FRFGIGK A2Q0M1_9VIRU IPQGSY MDTVKP QPVVLNHFHVRHYERISR FEGQGL A2Q0M3_9VIRU IPQGSY MDTVKP QPAVLLNRHIRHYERJ VEFGQEL A2Q0M4_9VIRU IFEGSY LDAIAP QPTVLRHGYDRHRSNI FIFGQGL O11874_CSV IDNWKY RGINKP GQQLMEDGTLGPKHFV FELGQGI Q5ZNS9_9VIRU LKIKSN DLRSNS QESEUGNSSSLVKKIH DYLGKRV Q5ZNZ4_9VIRU LPLGNF MKSKLP KLTYQNYLRLGEVPTT FFKGKGI Q66216_CSV MANWDY LGFGKP DQHSI FFKGEGI Q66236_CSV MANWDY LGFGKP DQHSI FFKGEGI Q80KH5_CSV IGNETN VHTTLP SRYEDGEISTRKFV WRFGSGL Q80KH6_CSV IVNETN VHTTLP SRYEDGEISTRKFV WRFGSGL Q80KH7_CSV IKHYHR RGVSKP GQEALPTSGVVGQEYT AVFESGL Q80KH8_CSV IFNWSN LHTITP HQQSLESGQVLPHDFI WRFGSGL Q80KH9_CSV LVTSHR LHTITP HQQSLESGQVLPHDFI WRFGSGL Q80PW5_CSV IAYNDY RFSLTT DHGLSTQGAQMSFEHT SVFDDSGV Q80873_9VIRU IGNYQP TESTKP RLEDRTSVRFGREEYI QRFLGGE Q89632_CSV IGHYQK VNADKP SKTVRYGDSKNVRKFI DRDDEGV Q91H14_9VIRU IKQFDH QGMNKP GEEAVPQLGLXGVEFT SVFDSGV Q98825_CSV IGNYQP JESTKP RLEDRTSVQFGRKEYT DRFFGGL A0HYV0_9ABAC TETGRN KYSYE SNA SAAFGF A8C6C4_NPVAP AETGAV QYSYE SGA SALFKF A9YMX2_9BBAC TEIGRN QYSYE SGA SAVFKY B0FDX4_9ABAC AETGAV VHNDE SGA SPVFNY CXOL2_NPVOP TETGRN QYSYS SGA SAAFGF CXOL_NPVAC AETGAV VHNDE SGA SPIFNY Q06KN7_NPVAG TETGRN KYSYE SGA SAVFKY Q0GYM0_9ABAC AETGAV VHNDE SGA SPIFNY Q5Y4P1_NPVAP AETGAV IHNDE SGA SPVFNY Q8JM47_9ABAC TETGRN KYSYE SGA SAAFGF Q8QLC7_9ABAC TDTGRN KYSYE SGA SAAFGF Q9PYR8_GVXN TETGRN QYSYE SGA SAAFKY Hypo_A AES VYIP TTTALLG S KNKV YNGIP circulin_F GES VWIP ISAAIG S KNKV YRAIP cycloviolecin_B16 AES VWIP TCTALLG S KDKV YNTIP cycloviolecin_B3 AES VYIP VTTVIG S KDKV YNGIP cycloviolecin_B4 AES VWIF TVTALLG S KDKV YNGIP cycloviolecin_H4 AES VWIF TVTALLG S SNNV YNGIP cycloviolecin_O1 AES VYIP TVTALLG S SNRV YNGIP cycloviolecin_O18 GES VYIP TVTALAG K KSKV YNGIP cycloviolecin_O7 GES VWIP IITALAG K KSKV YNSIP cycloviolecin_Y5 AES VWIP IVTALVG S SDKV YNGIP kalata_B16 AES VYIP TITALLG K QDKV YDGIP kalata_B17 AES VYIP TITALLG K KDQV YNGIP mram_3 GES VYLP FITUG K QGKV YHGIP vhri AES VWIP TVTALLG S SNKV YNGIP vibi_E AES VWIP TVTALIG S SNKV YNGIP violein_A GET FKFK YTPR S SYPV KSAIS HYfl_A GES VYIP TVTALLG T KDKV YLNSIS HYfl_F GET TIFN WIPN K NHHDKV YWNSIS HYfl_I GES VFIP ISGVIG S KSKV YRNGIP HYfl_J GES AYFG WIPG S RNKV YFNGIA HYfl_K GES VYIP FTAVVG T KDKV YLNGIP HYfl_L AES VYLP FTGVVG T KDKV YLNGIP circulin_A GES VWIP ISAAIG S KNKV YRNGIP circulin_C GES VFIP ITSVAG S KSKV YRNGIP circulin_D GES VWIP VTSIFN K KNKV YHDKIP circulin_E GES VFIP LTSVFN K KNKV YHDKIP cyclopsychotride_A GES VFIP TVTALLG S KSKV YKNSIP cycloviolein_B1 GES VYLP FTAPLG S SSKV YRNGIP cycloviolein_B10 GES VWIP LTSAIG S KSSV YRNGIP cycloviolein_B11 GES VLIP ISSVIG S KSAV YRNGVF cycloviolein_B13 IET YTFP ISEMIN S KNKV YRNGIF cycloviolein_B14 GES VWIP JSSAJG S KNKV QKNGAG cycloviolein_B15 GES VWIP ISGAIG S KSKV YRKGIP cycloviolein_B2 GES VWIP LTATIG S KSKV YRNGIP cycloviolein_B5 GER VIERTRAW RATVG I SLHTLE YRNGIP cycloviolein_B8 GEG VYLP FTAPLG S SSKV YRNGRL cycloviolein_B9 GES VWIP LTAAIG S SSKV YRNGIP cycloviolein_H1 GES VYIP LISAIG S KSKV YRNGIP cycloviolein_O10 GES VYIP LISAVG S KSKV YRNGIP cycloviolein_O13 GES VWIP JSAAIG S KSKV YRNGIP cycloviolein_O17 GES VWIP JSAAIG S KNKV YRNGIP cycloviolein_O2 GES VWIP ISSAIG S KSKV YRNGIP cycloviolein_O20 GES VWIP LTSAIG S KSKV YRNGIP cycloviolein_025 GET AFIP ITHVPGT S KSKV YRNGIP cycloviolein_O3 GES VWIP LTSAIG S KSKV YRNGIP cycloviolein_O9 GES VWIP ISSAIG S KNKV YRNGIP cycloviolein_O5 GES VWIP ISSAIG S KNKV YRNGTP cycloviolein_O9 GES VWIP LTSAVG S KSKV YRNGIP cycloviolein_Y4 GES VFIP ITGVTG S SSNV YLNGVP cycloviolein_B GES YVLP FTBG T TSSQ FKNGTA cycloviolein_C GES VFIP LITVAG S KNKV YRNGIP cycloviolein_D GES VFIP ISAAIG S KNKV YRNGFP hcf-1 GES HYIP VTSAIG S RNRS MRNGIP htf-1 GDS HYIP VTSAIG S TNGS MRNGIP kalata_B12 GDT FVLG NDSS S NYPI VRDGSL kalata_B18 AES VYIP ISIVLG S SNQV YRNGVP kalata_B5 GES VYIP ISGVIG S TDKV YLNGTT mram_2 AES VYIP LTSAIG S KSKV YRNGIP mram_8 GES VFIP LTSAIG S KSKV YRNGIP mram_9 GES VWIF LTSIVG S KNNV TLNGVP vhi-1 GES AMISF FTEVIG S KNKV YLNSIS vibi_I GES VWIP LTSTVG S KSKV YRNGIP vibi_K GES VWIP LTSAVG S KSKV YRNGIP vitri_A GES VWIP ITSAIG P KSKV YRNGIP Hyfl_D GES VYIP FTGIAG S KSKV YYNGSVP Hyfl_E GES VYLP FLPN S RNHV YLNGEIP Hyfl_M GES IFFP FNPG Y KDNL YYNGNIP PS-1 GET IWDKT HAAG S SVANI VRNGFIP circulin B GES VFIP ISTLLG S KNKV YRNGVIP cycloviolecin_B12 GES VFIP JSSVJG S KSKV YRNGVIP cycloviolecin_B17 GET TLGT YTVG S SWPI TRNGLPI cycloviolecin_B6 GET VGGT NTPG T SWPV TRNGLPI cycloviolecin_B7 GET VGGT NTPG G SWPV TRNGLFV cycloviolecin_H2 GES VYIP ETG A RNRV TRNGLFV cycloviolecin_H3 GET FGGT NIPG S DPWPV YLNSAJA cycloviolecin_O11 GES VWIP ISAVVG T KSKV TRNGLPV cycloviolecin_O12 GET VGGT NTPG S SWPV YKNGTLP cycloviolecin_O15 GET FTGK YTPG S SYPI TRNGLPI cycloviolecin_O16 GET TFGK YTPG S SYPI KKNGLVP cycloviolecin_O19 GES VWIP ISSVVG S KSKV KKINGLP cycloviolecin_O21 GET VTGS YTPG S SWPV YKDGTLP cycloviolecin_O22 GET VGGT NTPG T SWPV TRNGLPV cycloviolecin_O23 GET FGGT NTPG T DSSWPI TRNGLPT cycloviolecin_O24 GET FGGT NTPG T DPWPV THNGLPT cycloviolecin_O6 GES VWIP ISAAVG T KSKV THNGLPT cycloviolecin_O8 GES VWIP ISSVVG S KSKV YKNGTLP cycloviolin_A GES VFIP ISAAIG S KNKV YKNGTLP kalata_B1 GET VGGT NTPG S SWPV YRNGVIP kalata_B10 GET FGGT NTPG T SSWPI TRNGLPV kalata_B10_linear GET FGGT NTPG S SSWPI TRDGLPT kalata_B11 GET FGGT NTPG S TDPI TRDGLPT kalata_B13 GET FGGT NTPG S DPWPV TRDGLPV kalata_B14 GES FGGT NTPG A DPWPV TRDGLPV kalata_B15 GES FGGS NTPG A TWPI TRDGLPV kalata_B2 GET FGGT NTPG S TWPI TRDGLPV kalata_B3 GET FGGT NTPG S DPWPI TRDGLPV kalata_B4 GET VGGT NTPG T SWPV TRDGLPT kalata_B6 GET FGGT NTPG S SSWPI TRDGLPV kalata_B7 GET TLGT YTQG T SWPI TRDGLPT kalata_9 GET VGGT NTPG S SWPV TRDGLPV mram_1 GES VYIP ISSLLQ S KSKV TRDGLPV mram_10 GES VFIP YTPG S KNKV YKNOSIP mram_11 GET LLGT YTPG T KRPV YRNGVIP mram_13 GET VGNK ISSIVG T TWPV YKNGHPT mram_14 GEG VFIP ISSVVG S KSKV YRNGHPI mram_4 GES VFIP LISAIG S KSKV YKNGSIP mram_5 GES VFIP ISSLLG S SSWPI YKNGSIP mram_6 GES VYIP ISSIVG S SWPI YKNGSIP mram_7 GES VFIP NTPG S SWPV TRNGLPV varv_peptide_A GET VGGT NTPG S KSKV SRNGLPV varv_peptide_B GET FGGT NTPG S KRPV TRNGBPI varv_peptide_C GET VGGT NTPG S TWPV TRNGLPI varv_peptide_D GET VGGS NTPG S KSKV TRNGLPI varv_peptide_E GET VGGT YTAG S KNKV TRNGVPI varv_peptide_F GET VIGT NTPG S KSKV SRNGVPV varv_peptide_G GET FGGT NTPG S KSKV SRNGVPV varv_peptide_H GET FGGT NTPG S SWPV TRNGLPV vhi-2 GET FTGT YTNG T DPWPM TRNGLPV vibi_A GET FGGT NTPG S SWPV TRNGLPV vibi_B GET FGGT NTPG T SWPV TRNGLPV vibi_C GET AFGS YTPG S SWPV TRNGLPV vibi_D GET FGGR NTPG T SWPV TRNGLPV vibi_F GET VFIP LISALG S KSKV YKNGIIP vibi_G GET VFIP LTSAIG S KSKV YKNGIFP vibi_H AES VYIP LTIVIG S KSKV YKNGILP vibi_I CES VWIP ISEVIG A KSKV YKNGTFP vico_A AES VYIP FTGIAG S KNKV YYNGSIP vico_B AES VYIP ITGIAG S KNKV YYNGSIP viciapeptide_1 GET VGGT NTPG S SRPV TXNGLPV vodo_M GES FTGK YTVQ S SWPV TRNGAPI vodo_N GET TLGK YTAG S SWPV YRNGLPV CD-1 GES YVIP ISYLVG S DTIFKV KRNGADGF Hyfl_B AET FIGK YTEELG T TAFL MKNGSPRQ Hyfl_C AET FIGK YTEELG T TAFL MKNGSPRQ cycloviolecin_O14 GES FKGK YTPG S SKYPL AKNGSIPA kalata_B8 GET LLGT YTPG T NKYRV TKDGSVLN kalata_B9 GET VLGT YTPG T NIYRV TKDGSVFN kalata_B9_linear GET VLGT YTPG T NIYRV TKDGSVLN mram_12 GES TLGE YTPG T SWPI TKNGSAIL palicourein GET RVIPV TYSAAIG T DDRSDGL KRNGDPTE cycloviolecin_Y1 GET FLGR YTPG S GNYGF YGTNGGTIFD cycloviolecin_Y2 GES FLGR YTAG S GNWGL YGTNGGTIFD cycloviolecin_Y3 GET FLGR YTAG S GNWGL YGTNGGTIFD tricyclo_A GES FLGR YTKG S GEWKL YGTNGGTIFD tricyclo_B GES FLGR YTKG S GEWKL YGENGGTIFD

indicates data missing or illegible when filed 

1. An isolated nucleic acid molecule comprising a sequence of nucleotides encoding a linear precursor form of a cyclic cystine knot polypeptide, wherein said linear precursor form comprises an amino acid sequence comprising a signal peptide, a cystine knot polypeptide, and a non-cystine knot polypeptide, wherein said cystine knot polypeptide in its mature form comprises the structure:

wherein C₁ to C₆ are cysteine residues; wherein each of C₁ and C₄, C₂ and C₅, and C₃ and C₆ are connected by a disulfide bond to form a cystine knot; wherein each X represents an amino acid residue in a loop, wherein said amino acid residues may be the same or different; wherein d is about 1-2; wherein for a, b, c, e, and f, and i) a may be any number from 3-10, and ii) b, c, e, and f may be any number from 1 to
 20. 2. The isolated nucleic acid of claim 1, wherein in the cyclic form of said cystine knot polypeptide, loop 6 has an amino acid sequence selected from the group consisting of YRNGVIP, YLNGVIP, YLDGVP, YLNGIP, YLDGIP, YLNGLP, YNNGLP, YNDGLP, YINGTVP, YIDGTVP, YNHEP, YDHEP, LKNGSAF, MKNGLP, YRNGIP, YKNGIP, and YRDGVIP.
 3. The isolated nucleic acid of claim 1, wherein in said amino acid sequence of said linear precursor form, a linker peptide comprising 2 or more amino acids connects said non-cystine knot polypeptide with the C-terminal amino acid of said cystine knot polypeptide.
 4. The isolated nucleic acid molecule of claim 1, wherein said non-cystine knot polypeptide comprises an albumin polypeptide.
 5. The isolated nucleic acid molecule of claim 4, wherein said albumin polypeptide comprises an albumin a-chain.
 6. The isolated nucleic acid molecule of claim 1, wherein in said amino acid sequence of said linear precursor form, said signal peptide is adjacent to the N-terminal amino acid of said cystine knot polypeptide.
 7. The isolated nucleic acid molecule of claim 1, wherein said nucleic acid sequence encoding a linear precursor form of a cystine knot polypeptide is from a plant of family Fabaceae.
 8. The isolated nucleic acid molecule of claim 7, wherein said nucleic acid sequence encoding a linear precursor form of a cystine knot polypeptide is from Clitoria ternatea.
 9. The isolated nucleic acid molecule of claim 1, wherein in said amino acid sequence of said linear precursor form, said signal peptide is encoded by a nucleotide sequence selected from the group consisting of SEQ ID NOS:127, 150, 152, 154, 156, 158 and
 160. 10. An isolated nucleic acid molecule encoding a proteinaceous molecule having a cystine knot backbone and a defined biological activity, comprising a sequence of nucleotides encoding a linear precursor form of a cyclic cystine knot polypeptide operably linked to a promoter, wherein said linear precursor form comprises an amino acid sequence comprising: a signal peptide, a cystine knot polypeptide and a non-cystine knot polypeptide, wherein said cystine knot polypeptide in its mature form comprises the structure:

wherein C₁ to C₆ are cysteine residues; wherein each of C₁ and C₄, C₂ and C₅, and C₃ and C₆ are connected by a disulfide bond to form a cystine knot; wherein each X represents an amino acid residue in a loop, wherein said amino acid residues may be the same or different; wherein d is about 1-2; wherein one or more of loops 1, 2, 3, 5 or 6 have an amino acid sequence comprising the sequence of a heterologous peptide comprising a plurality of contiguous amino acids and having a defined biological activity and wherein said peptide is about 2 to 30 amino acid residues, wherein any loop comprising said sequence of said peptide comprises 2 to about 30 amino acids, and wherein for any of loops 1, 2, 3, 5, or 6 that do not contain said sequence of said peptide, a, b, c, e, and f, may be the same or different, a may be any number from 3-10, and b, c, e, and f may be any number from 1 to
 20. 11. The isolated nucleic acid of claim 10, wherein said amino acid sequence of said heterologous peptide comprises a portion of an amino acid sequence of a larger protein, wherein said peptide confers said defined biological activity on said larger protein.
 12. The isolated nucleic acid molecule of claim 1 or claim 10, wherein said non-cystine knot polypeptide comprises an albumin polypeptide.
 13. The isolated nucleic acid molecule of claim 10, wherein said albumin polypeptide comprises an albumin a-chain.
 14. The isolated nucleic acid molecule of claim 1 or claim 10, wherein in said amino acid sequence of said precursor form, said signal peptide is adjacent to the N-terminal amino acid of the mature form of said cystine knot polypeptide.
 15. A method for producing a cystine knot polypeptide, comprising: transforming a host cell with a vector comprising a nucleic acid molecule according to claim 1 or claim 10, wherein said precursor form of said cystine knot polypeptide is expressed.
 16. A method for producing a cyclic cystine knot polypeptide, comprising: i) transforming a host cell with a vector comprising an isolated nucleic acid molecule according to claim 1 or claim 10, ii) expressing a linear precursor form of a cystine knot polypeptide; and iii) processing said linear precursor form to form a cyclic cystine knot polypeptide having the structure:


17. The method of claim 16, wherein said host cell is a plant cell.
 18. The method of claim 17, wherein said plant cell is from the plant family Fabaceae.
 19. The method of claim 15, wherein said host cell carries an enzyme for processing said precursor form of said cystine knot polypeptide to produce a cyclic cystine knot polypeptide.
 20. The method of claim 16, wherein said host cell carries an enzyme for processing said precursor form of said cystine knot polypeptide to produce a cyclic cystine knot polypeptide.
 21. A composition comprising a host cell comprising a heterologous nucleic acid comprising the isolated nucleic acid of claim 1 or claim
 10. 